Should we add atorvastatin to irbesartan for improving renoprotective effects in early diabetic nephropathy? A meta-analysis of randomized controlled trials.
Zuo Ying,Li Ting,Lei Zhen
Angiotensin II receptor blocker has exhibited their renal protective benefits in diabetic nephropathy. This meta-analysis aimed to evaluate the effects of adding atorvastatin to irbesartan in early diabetic nephropathy. A systematic literature search was performed in PubMed, Embase, Cochrane Library, CNKI, VIP, and Wanfang database until March 25, 2019. Randomized controlled trials evaluating the effects of adding atorvastatin to irbesartan in early diabetic nephropathy were eligible. Primary endpoint was urinary albumin excretion rate, serum creatinine, and blood urea nitrogen. Serum level of total cholesterol, triglyceride, fasting blood glucose, interleukin-6,and C-reactive protein (CRP) as well as blood pressure were secondary endpoints. Seventeen trials involving 1,390 patients were identified. Compared with irbesartan alone, co-administration of atorvastatin and irbesartan significantly reduced urinary albumin excretion rate (weighted mean differences [WMD] -21.22 μg/min; 95% confidence interval [CI] -26.95 to -15.50), serum creatinine (WMD -6.46 μmol/L; 95%CI -8.52 to 4.39),BUN (WMD -0.46 mmol/L; 95%CI -0.64 to -0.27), total cholesterol (WMD -1.79 mmol/L; 95%CI -2.34 to -1.23), triglyceride (WMD -0.93 mmol/L; 95%CI -1.20 to -0.67),and systolic blood pressure (WMD -2.27 mmHg; 95%CI -4.01 to -0.53), CRP (standard mean difference [SMD] 1.57; 95%CI -2.24 to -0.9), and Interleukin-6 (SMD 1.53; 95%CI -2.29 to -0.78). However, there was a significantly increased risk of nausea/vomiting (risk ratio 3.15; 95% CI 1.18-8.38) on the co-administration group. In conclusion, adding atorvastatin to irbesartan achieves additional renal protective benefits in early diabetic nephropathy patients. However, these findings should be interpreted with caution due to suboptimal methodological quality of the analyzed trials.
Metabolomic Markers of Kidney Function Decline in Patients With Diabetes: Evidence From the Chronic Renal Insufficiency Cohort (CRIC) Study.
Kwan Brian,Fuhrer Tobias,Zhang Jing,Darshi Manjula,Van Espen Benjamin,Montemayor Daniel,de Boer Ian H,Dobre Mirela,Hsu Chi-Yuan,Kelly Tanika N,Raj Dominic S,Rao Panduranga S,Saraf Santosh L,Scialla Julia,Waikar Sushrut S,Sharma Kumar,Natarajan Loki,
American journal of kidney diseases : the official journal of the National Kidney Foundation
RATIONALE & OBJECTIVE:Biomarkers that provide reliable evidence of future diabetic kidney disease (DKD) are needed to improve disease management. In a cross-sectional study, we previously identified 13 urine metabolites that had levels reduced in DKD compared with healthy controls. We evaluated associations of these 13 metabolites with future DKD progression. STUDY DESIGN:Prospective cohort. SETTING & PARTICIPANTS:1,001 Chronic Renal Insufficiency Cohort (CRIC) participants with diabetes with estimated glomerular filtration rates (eGFRs) between 20 and 70mL/min/1.73m were followed up prospectively for a median of 8 (range, 2-10) years. PREDICTORS:13 urine metabolites, age, race, sex, smoked more than 100 cigarettes in lifetime, body mass index, hemoglobin A level, blood pressure, urinary albumin, and eGFR. OUTCOMES:Annual eGFR slope and time to incident kidney failure with replacement therapy (KFRT; ie, initiation of dialysis or receipt of transplant). ANALYTICAL APPROACH:Several clinical metabolite models were developed for eGFR slope as the outcome using stepwise selection and penalized regression, and further tested on the time-to-KFRT outcome. A best cross-validated (final) prognostic model was selected based on high prediction accuracy for eGFR slope and high concordance statistic for incident KFRT. RESULTS:During follow-up, mean eGFR slope was-1.83±1.92 (SD) mL/min/1.73m per year; 359 (36%) participants experienced KFRT. Median time to KFRT was 7.45 years from the time of entry to the CRIC Study. In our final model, after adjusting for clinical variables, levels of metabolites 3-hydroxyisobutyrate (3-HIBA) and 3-methylcrotonyglycine had a significant negative association with eGFR slope, whereas citric and aconitic acid were positively associated. Further, 3-HIBA and aconitic acid levels were associated with higher and lower risk for KFRT, respectively (HRs of 2.34 [95% CI, 1.51-3.62] and 0.70 [95% CI, 0.51-0.95]). LIMITATIONS:Subgroups for whom metabolite signatures may not be optimal, nontargeted metabolomics by flow-injection analysis, and 2-stage modeling approaches. CONCLUSIONS:Urine metabolites may offer insights into DKD progression. If replicated in future studies, aconitic acid and 3-HIBA could identify individuals with diabetes at high risk for GFR decline, potentially leading to improved clinical care and targeted therapies.
Metformin prevents the development of severe chronic kidney disease and its associated mineral and bone disorder.
Neven Ellen,Vervaet Benjamin,Brand Kerstin,Gottwald-Hostalek Ulrike,Opdebeeck Britt,De Maré Annelies,Verhulst Anja,Lalau Jean-Daniel,Kamel Said,De Broe Marc E,D'Haese Patrick C
Chronic kidney disease (CKD) causes dysregulation of mineral metabolism, vascular calcification and renal osteodystrophy, an entity called 'CKD-Mineral and Bone Disorder' (CKD-MBD). Here we determine whether metformin, an anti-diabetic drug, exerts favorable effects on progressive, severe CKD and concomitant mineral metabolism disturbances. Rats with CKD-MBD, induced by a 0.25% adenine diet for eight weeks, were treated with 200 mg/kg/day metformin or vehicle from one week after CKD induction onward. Severe, stable CKD along with marked hyperphosphatemia and hypocalcemia developed in these rats which led to arterial calcification and high bone turnover disease. Metformin protected from development toward severe CKD. Metformin-treated rats did not develop hyperphosphatemia or hypocalcemia and this prevented the development of vascular calcification and inhibited the progression toward high bone turnover disease. Kidneys of the metformin group showed significantly less cellular infiltration, fibrosis and inflammation. To study a possible direct effect of metformin on the development of vascular calcification, independent of its effect on renal function, metformin (200 mg/kg/day) or vehicle was dosed for ten weeks to rats with warfarin-induced vascular calcification. The drug did not reduce aorta or small vessel calcification in this animal model. Thus, metformin protected against the development of severe CKD and preserved calcium phosphorus homeostasis. As a result of its beneficial impact on renal function, associated comorbidities such as vascular calcification and high bone turnover disease were also prevented.
Oral Magnesium Supplementation Improved Lipid Profile but Increased Insulin Resistance in Patients with Diabetic Nephropathy: a Double-Blind Randomized Controlled Clinical Trial.
Sadeghian Mehdi,Azadbakht Leila,Khalili Noushin,Mortazavi Mojgan,Esmaillzadeh Ahmad
Biological trace element research
Low serum magnesium concentrations were associated with development of renal failure. We aimed to determine whether magnesium supplementation improves renal function, insulin resistance, and metabolic profiles in patients with diabetic nephropathy. A total of 80 hypomagnesemic patients diagnosed with type 2 diabetes and early-stage nephropathy were recruited. Subjects received either daily magnesium oxide or placebo for 12 weeks. Biochemical and anthropometric variables were measured. Physical activity and dietary intakes were also recorded. This study was approved by the ethics committee of Isfahan University of Medical Sciences and was registered on the Iranian Registry of Clinical Trials website (IRCT registration no. IRCT201404271485N12). Serum magnesium levels were not changed significantly. Although the supplementation did not influence glycemic indices, patients in the magnesium group had greater insulin resistance compared with the placebo group after intervention (0.3 ± 2.3 μIU/mL vs. - 0.04 ± 2.05, P = 0.04). No significant changes were observed in serum total cholesterol, triglycerides, HDL, LDL, and total cholesterol/HDL cholesterol ratio. Furthermore, magnesium did not affect inflammation, serum levels of creatinine, and blood urine nitrogen. However, a marginal decrease in microalbuminuria (- 3.1 ± 2.2 mg/L vs. - 14 ± 9.9, P = 0.09) was observed. Oral magnesium supplementation slightly improved microalbuminuria but resulted in increased insulin resistance in patients with diabetic nephropathy.
Dietary low-fat soy milk powder retards diabetic nephropathy progression via inhibition of renal fibrosis and renal inflammation.
Jheng Huei-Fen,Hirotsuka Motohiko,Goto Tsuyoshi,Shibata Masayuki,Matsumura Yasuki,Kawada Teruo
Molecular nutrition & food research
SCOPE:Diabetic nephropathy (DN) is a major cause of end-stage renal disease. Here, we examined the effect of long-term consumption of a low-fat soy milk powder (LFSMP) on the diabetic kidney structure and function. METHODS AND RESULTS:KKAy mice were fed a casein-, LFSMP-, or high-fat soy mixture powder (HFSMP)-based diet for 4 months. Plasma and urine were subjected to a biochemical assay every 2-4 wk. Renal morphology and protein expression were evaluated by histochemical staining and western blots. Although HFSMP-based diet showed no protective effect on DN. LFSMP-fed mice exhibited lower water intake, urine output, and urinary albumin, and glucose excretion. Furthermore, strong preservation of renal structural proteins and low urinary N-acetyl-beta-d-glucosaminidase activity were observed in LFSMP-fed mice, indicating alleviation of renal injury. LFSMP-fed mice showed a lesser degree of mesangial matrix expansion, of tubulointerstitial fibrosis, and of myofibroblast differentiation. Finally, milder renal inflammation was found in LFSMP-fed mice, as evidenced by a decrease in urinary monocyte chemoattractant protein- 1 excretion and lesser macrophage infiltration into the tubulointerstitium. CONCLUSION:The present data suggests that long-term consumption of LFSMP but not HFSMP retards DN progression via suppressing renal injury, myofibroblast differentiation, and renal macrophage infiltration in diabetic condition.
Bergenin ameliorates diabetic nephropathy in rats via suppressing renal inflammation and TGF-β1-Smads pathway.
Yang Jing,Kan Ming,Wu Gui Yong
Immunopharmacology and immunotoxicology
CONTEXT:Diabetic nephropathy (DN) is a serious complication of diabetes. Bergenin (BEG) was previously confirmed to be effective in treating type 2 diabetes in rats. OBJECTIVE:The objective of this study was to investigate the effects of BEG on renal function in diabetic rats, and meanwhile explore the molecular mechanism. METHODS:DN was induced in rats by a single intraperitoneal injection of streptozotocin. The renal function was evaluated by serum creatinine (SCr), blood urea nitrogen (BUN), urinary albumin and renal histopathology. The proliferation of mesangial cells (MCs) was assayed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H tetrazolium bromide. The production of inflammatory cytokines was detected by ELISA kits, and the levels of Smads were measured by western blotting. RESULTS AND CONCLUSION:In DN rats, there were significantly increased levels of SCr, BUN, urinary albumin, plasma glucose and renal index. The histological changes in diabetic kidney revealed noteworthy focal mesangial matrix expansion. In vitro experiment, high glucose markedly promoted MCs proliferation. However, treatment with BEG obviously normalized these functional parameters, improved diabetic histological changes in vivo and inhibited MCs' proliferation in vitro. Moreover, the levels of tumor necrosis factor-alpha, interleukin-1 (IL-1) and IL-6 in BEG-treated renal tissue and MCs were both reduced. Finally, it showed that BEG markedly reduced transforming growth factor-β1 (TGF-β1) production, down-regulated p-Smad2/3 expression and promoted Smad7 expression both in vivo and in vitro. In conclusion, BEG exerts the effective protective role against kidney injuries of diabetic rat, in which the underlying mechanisms are associated with reducing renal inflammation and blocking TGF-β1-Smads pathway.
Interleukin-18 and diabetic nephropathy: A review.
Yaribeygi Habib,Atkin Stephen L,Sahebkar Amirhossein
Journal of cellular physiology
The inflammatory response has an important role in the pathophysiology of diabetic nephropathy that is contributed to by inflammatory mediators such as interleukin-1 (IL-1), IL-6, IL-18, tumor necrosis factor-α, and macrophage chemotactic protein-1; however, the role of IL-18 seems to be more specific than other cytokines in the inflammatory process. IL-18 is expressed in renal tissue and is upregulated by several stimuli including hyperglycemia. The expression/urinary level of IL-18 is positively correlated with the progression of diabetic nephropathy and the urinary albumin excretion rate. In this review, we have focused on the molecular pathways modulating the relationship between IL-18 and diabetic nephropathy.
Exogenous kallikrein protects against diabetic nephropathy.
Liu Wenjuan,Yang Yeping,Liu Yemei,Lu Xiaolan,Guo Shizhe,Wu Meng,Wang Meng,Yan Linling,Wang Qinghua,Zhao Xiaolong,Tong Xian,Hu Ji,Li Yiming,Hu Renming,Stanton Robert C,Zhang Zhaoyun
The kallikrein-kinin system has been shown to be involved in the development of diabetic nephropathy, but specific mechanisms are not fully understood. Here, we determined the renal-protective role of exogenous pancreatic kallikrein in diabetic mice and studied potential mechanisms in db/db type 2 diabetic and streptozotocin-induced type 1 diabetic mice. After the onset of diabetes, mice were treated with either pancreatic kallikrein (db/db+kallikrein, streptozotocin+kallikrein) or saline (db/db+saline, streptozotocin+saline) for 16 weeks, while another group of streptozotocin-induced diabetic mice received the same treatment after onset of albuminuria (streptozotocin'+kallikrein, streptozotocin'+saline). Db/m littermates or wild type mice were used as non-diabetic controls. Pancreatic kallikrein had no effects on body weight, blood glucose and blood pressure, but significantly reduced albuminuria among all three groups. Pathological analysis showed that exogenous kallikrein decreased the thickness of the glomerular basement membrane, protected against the effacement of foot process, the loss of endothelial fenestrae, and prevented the loss of podocytes in diabetic mice. Renal fibrosis, inflammation and oxidative stress were reduced in kallikrein-treated mice compared to diabetic controls. The expression of kininogen1, tissue kallikrein, kinin B1 and B2 receptors were all increased in the kallikrein-treated compared to saline-treated mice. Thus, exogenous pancreatic kallikrein both prevented and ameliorated diabetic nephropathy, which may be mediated by activating the kallikrein-kinin system.
Rice bran protein hydrolysates attenuate diabetic nephropathy in diabetic animal model.
Boonloh Kampeebhorn,Lee Eun Soo,Kim Hong Min,Kwon Mi Hye,Kim You Mi,Pannangpetch Patchareewan,Kongyingyoes Bunkerd,Kukongviriyapan Upa,Thawornchinsombut Supawan,Lee Eun Young,Kukongviriyapan Veerapol,Chung Choon Hee
European journal of nutrition
INTRODUCTION:Diabetic nephropathy (DN) is an important microvascular complication of uncontrolled diabetes. The features of DN include albuminuria, extracellular matrix alterations, and progressive renal insufficiency. Rice bran protein hydrolysates (RBPs) have been reported to have antihyperglycemic, lipid-lowering, and anti-inflammatory effects in diabetic rats. Our study was to investigate the renoprotective effects of RBP in diabetic animals and mesangial cultured cells. METHODS:Eight-week-old male db/m and db/db mice were orally treated with tap water or RBP (100 or 500 mg/kg/day) for 8 weeks. At the end of the experiment, diabetic nephropathy in kidney tissues was investigated for histological, ultrastructural, and clinical chemistry changes, and biomarkers of angiogenesis, fibrosis, inflammation, and antioxidant in kidney were analyzed by Western blotting. Protection against proangiogenic proteins and induction of cytoprotection by RBP in cultured mesangial cells was evaluated. RESULTS:RBP treatment improved insulin sensitivity, decreased elevated fasting serum glucose levels, and improved serum lipid levels and urinary albumin/creatinine ratios in diabetic mice. RBP ameliorated the decreases in podocyte slit pore numbers, thickening of glomerular basement membranes, and mesangial matrix expansion and suppressed elevation of MCP-1, ICAM-1, HIF-1α, VEGF, TGF-β, p-Smad2/3, and type IV collagen expression. Moreover, RBP restored suppressed antioxidant Nrf2 and HO-1 expression. In cultured mesangial cells, RBP inhibited high glucose-induced angiogenic protein expression and induced the expression of Nrf2 and HO-1. CONCLUSION:RBP attenuates the progression of diabetic nephropathy and restored renal function by suppressing the expression of proangiogenic and profibrotic proteins, inhibiting proinflammatory mediators, and restoring the antioxidant and cytoprotective system.
Crocin improves renal function by declining Nox-4, IL-18, and p53 expression levels in an experimental model of diabetic nephropathy.
Yaribeygi Habib,Mohammadi Mohammad T,Rezaee Ramin,Sahebkar Amirhossein
Journal of cellular biochemistry
Oxidative damage, inflammation and apoptosis play significant roles in diabetic nephropathy. Previous studies demonstrated anti-inflammatory and anti-oxidative effects of crocin, but there is no evidence about its effects on IL-18, NOX-4, and p53 expression in diabetic kidneys. The aim of this study was to evaluate possible effects of crocin on improving main mechanisms underlying diabetic nephropathy. Male Wistar rats were randomly divided into four separate groups as normal (C), normal treated (CC), diabetic (D), and diabetic treated (DC) (n = 6). Diabetes was induced by a single dose of streptozotocin (40 mg/kg/intravenous). Treated groups received crocin (40 mg/kg, intraperitoneal) for 8 weeks. At the end of the 8th week of the study, all rats were sacrificed and urine, blood and tissue were collected. Levels of urea, uric acid, creatinine and glucose were determined collected sera, and proteinuria was measured in urine samples. Moreover, the contents of malondialdehyde (MDA), nitrate, and glutathione (GLT) as well as catalase (CAT) and superoxide dismutase (SOD) enzymes activities were measured. The expression of NOX-4, IL-18, and p53 at both mRNA and protein levels were also assessed. Hyperglycemia significantly increased proteinuria in diabetic rats (D). Also, depressed antioxidant defense system potency, but increased NOX-4 expression and free radicals production resulting in oxidative stress, were observed. Moreover, expressions of IL-18 (as a marker of inflammation) and p53 (as a marker of apoptosis) were increased. These outcomes were accompanied by enhanced histological damages and renal failure but, treatment with crocin improved these deteriorations, and ameliorated renal function. It potentiated renal cells antioxidant defense system and declined inflammation. Also, crocin lowered apoptosis and improved histological damages in renal cells. Oxidative stress, inflammation and apoptosis are considered three main mechanisms underlying diabetic nephropathy. Treatment with crocin prevented these deleterious effects and improved renal function under diabetic conditions.
Inflammation-activated CXCL16 pathway contributes to tubulointerstitial injury in mouse diabetic nephropathy.
Hu Ze-Bo,Ma Kun-Ling,Zhang Yang,Wang Gui-Hua,Liu Liang,Lu Jian,Chen Pei-Pei,Lu Chen-Chen,Liu Bi-Cheng
Acta pharmacologica Sinica
Inflammation and lipid disorders play crucial roles in synergistically accelerating the progression of diabetic nephropathy (DN). In this study we investigated how inflammation and lipid disorders caused tubulointerstitial injury in DN in vivo and in vitro. Diabetic db/db mice were injected with 10% casein (0.5 mL, sc) every other day for 8 weeks to cause chronic inflammation. Compared with db/db mice, casein-injected db/db mice showed exacerbated tubulointerstitial injury, evidenced by increased secretion of extracellular matrix (ECM) and cholesterol accumulation in tubulointerstitium, which was accompanied by activation of the CXC chemokine ligand 16 (CXCL16) pathway. In the in vitro study, we treated HK-2 cells with IL-1β (5 ng/mL) and high glucose (30 mmol/L). IL-1β treatment increased cholesterol accumulation in HK-2 cells, leading to greatly increased ROS production, ECM protein expression levels, which was accompanied by the upregulated expression levels of proteins in the CXCL16 pathway. In contrast, after CXCL16 in HK-2 cells was knocked down by siRNA, the IL-1β-deteriorated changes were attenuated. In conclusion, inflammation accelerates renal tubulointerstitial lesions in mouse DN via increasing the activity of CXCL16 pathway.
Fenofibrate improves renal function by amelioration of NOX-4, IL-18, and p53 expression in an experimental model of diabetic nephropathy.
Yaribeygi Habib,Mohammadi Mohammad T,Rezaee Ramin,Sahebkar Amirhossein
Journal of cellular biochemistry
Among several pathological mechanisms involved in diabetic nephropathy, oxidative stress, inflammation, and apoptosis play a prominent role. Fenofibrate, a peroxisome proliferator-activated receptor-α (PPAR-α) agonist, has markedly improved oxidative stress and inflammatory responses, but there is no evidence about its effects on interleukin-18 (IL-18), NADPH oxidase type 4 (NOX-4), and p53 expression in diabetic kidneys. The aim of this study was to evaluate possible effects of fenofibrate on improving the underlying mechanisms of diabetic nephropathy. Male Wistar rats were randomly divided into four groups namely, normal, normal treated, diabetic and diabetic treated (N = 6). Diabetes was induced by a single dose of streptozotocin (40 mg/kg; IV). Treated animals received fenofibrate for 8 weeks daily (80 mg/kg; po). All groups were sacrificed on day 56 and blood, urine, and tissue samples were collected. Serum levels of urea, uric acid, creatinine, and glucose were assessed. Then, serum levels of malondialdehyde (MDA), nitrate, and glutathione (GLT), as well as the activities of catalase (CAT) and superoxide dismutase (SOD) enzymes were measured. The expression level of NOX-4, IL-18, and p53 proteins at both mRNA and protein levels were evaluated. Diabetes significantly increased albuminuria, free radicals production, inflammation, and apoptosis in non-treated rats while lowered antioxidant capacity. Moreover, diabetes caused histological damages leading to renal failure. Treatment with fenofibrate improved renal function by improving creatinine clearance (P = 0.01) and protein excretion (P = 0.001) and lowering plasma levels of blood urea nitrogen (P = 0.001), creatinine (P = 0.001), and uric acid (P = 0.01). Fenofibrate potentiated antioxidant defense systems by enhancing CAT (P = 0.01) and SOD (P = 0.01) enzymes activities and GLT content (P = 0.01), and reduced oxidative damage by lowering MDA generation (P = 0.02). Fenofibrate also attenuated the expression of NOX-4 (P = 0.05), IL-18 (P = 0.05), and p53 (P = 0.05) at both mRNA and protein levels. In conclusion, treatment with fenofibrate improved renal function by suppression of oxidative stress, attenuation of inflammation, and inhibition of apoptosis.
Increased sphingosine 1-phosphate mediates inflammation and fibrosis in tubular injury in diabetic nephropathy.
Yaghobian Dania,Don Anthony S,Yaghobian Sarina,Chen Xinming,Pollock Carol A,Saad Sonia
Clinical and experimental pharmacology & physiology
Hyperglycemia induces all isoforms of transforming growth factor β (TGFβ), which in turn play key roles in inflammation and fibrosis that characterize diabetic nephropathy. Sphingosine 1-phosphate (S1P) is a signaling sphingolipid, derived from sphingosine by the action of sphingosine kinase (SK). S1P mediates many biological processes, which mimic TGFβ signaling. To determine the role of SK1 and S1P in inducing fibrosis and inflammation, and the interaction with TGFβ-1, 2 and 3 signalling in diabetic nephropathy, human proximal tubular cells (HK2 cells) were exposed to normal (5 mmol/L) or high (30 mmol/L) glucose or TGFβ-1, -2, -3 ± an SK inhibitor (SKI-II) or SK1 siRNA. Control and diabetic wild type (WT) and SK1(-/-) mice were studied. Fibrotic and inflammatory markers, and relevant downstream signalling pathways were assessed. SK1 mRNA and protein expression was increased in HK2 cells exposed to high glucose or TGFβ1,-2,-3. All TGFβ isoforms induced fibronectin, collagen IV and macrophage chemoattractant protein 1 (MCP1), which were reversed by both SKI-II and SK1 siRNA. Exposure to S1P increased phospho-p44/42 expression, AP-1 binding and NFkB phosphorylation. WT diabetic mice exhibited increased renal cortical S1P, fibronectin, collagen IV and MCP1 mRNA and protein expression compared to SK1(-/-) diabetic mice. In summary, this study demonstrates that inhibiting the formation of S1P reduces tubulointerstitial renal inflammation and fibrosis in diabetic nephropathy.
Dibenzoylmethane ameliorates lipid-induced inflammation and oxidative injury in diabetic nephropathy.
Lee Eun Soo,Kwon Mi-Hye,Kim Hong Min,Kim Nami,Kim You Mi,Kim Hyeon Soo,Lee Eun Young,Chung Choon Hee
The Journal of endocrinology
Dibenzoylmethane (DBM) is a beta-diketone analog of curcumin. Numerous studies have shown the beneficial effects of curcumin on diabetes, obesity and diabetic complications including diabetic nephropathy. Recently, we investigated the beneficial metabolic effects of DBM on high-fat diet-induced obesity. However, the effects and mechanisms of action of DBM in the kidney are currently unknown. To investigate the renoprotective effects of DBM in type 2 diabetes, we administered DBM (100 mg/kg) orally for 12 weeks to high-fat diet-induced diabetic model mice. We used mouse renal mesangial (MES13) and macrophage (RAW 264.7) cells to examine the mechanism of action of DBM (20 μM). After DBM treatment, the albumin-to-creatinine ratio was significantly decreased compared to that of the high-fat-diet group. Moreover, damaged renal ultra-structures and functions including increased glomerular volume, glomerular basement membrane thickness and inflammatory signals were ameliorated after DBM treatment. Stimulation of MES13 and RAW264.7 cells by palmitate or high-dose glucose with lipopolysaccharides increased inflammatory signals and macrophage migration. However, these changes were reversed by DBM treatment. In addition, DBM inhibited NADPH oxidase 2 and 4 expression and oxidative DNA damage. Collectively, these data suggested that DBM prevented diabetes-induced renal injury through its anti-inflammatory and antioxidant effects.
Deletion of Smad3 prevents renal fibrosis and inflammation in type 2 diabetic nephropathy.
Xu Bi-Hua,Sheng Jingyi,You Yong-Ke,Huang Xiao-Ru,Ma Ronald C W,Wang Qingwen,Lan Hui-Yao
Metabolism: clinical and experimental
BACKGROUND:Transforming growth factor (TGF)-β/Smad3 signaling is highly activated in kidneys of patients with type 2 diabetic nephropathy (T2DN), however, the precise role of Smad3 in the pathogenesis of diabetic nephropathy remains unclear. METHODS:Smad3 knockout (KO)-db/db mice were generated by intercrossing of male and female double-heterozygous Smad3 db/m mice. Renal functions including urinary albumin excretion and serum creatinine were determined. Renal histological injury including renal fibrosis and inflammation were examined by periodic acid Schiff (PAS), periodic acid-silver methenamine (PASM), and immunohistochemistry (IHC) staining. RESULTS:Smad3 knockout (KO)-db/db mice were protected from the development of diabetic kidney injury, characterized by the normal levels of urinary albumin excretion and serum creatinine without any evidence for renal fibrosis and inflammation. In contrast, Smad3 wild-type (WT) db/db and Smad3 db/db mice developed progressively decline in renal function over the 12 to 32-week time course, including increased microalbuminuria and elevated levels of serum creatinine. Pathologically, Smad3 WT db/db and Smad3 db/db mice exhibited a marked deposition of collagen-I (colI), collagen-IV(col-IV), and an increased infiltration of F4/80 macrophages in kidney. Mechanistically, Smad3 deficiency decreased the lncRNA Erbb4-IR transcription, while increased miR-29b transcription and therefore protected the kidney from progressive renal injury in db/db mice. CONCLUSION:Results from this study imply that Smad3 may represent as a novel and effective therapeutic target for T2DN.
Endothelial heparan sulfate deficiency reduces inflammation and fibrosis in murine diabetic nephropathy.
Talsma Ditmer T,Katta Kirankumar,Ettema Marieke A B,Kel Berna,Kusche-Gullberg Marion,Daha Moh R,Stegeman Coen A,van den Born Jacob,Wang Lianchun
Laboratory investigation; a journal of technical methods and pathology
Inflammation plays a vital role in the development of diabetic nephropathy, but the underlying regulatory mechanisms are only partially understood. Our previous studies demonstrated that, during acute inflammation, endothelial heparan sulfate (HS) contributes to the adhesion and transendothelial migration of leukocytes into perivascular tissues by direct interaction with L-selectin and the presentation of bound chemokines. In the current study, we aimed to assess the role of endothelial HS on chronic renal inflammation and fibrosis in a diabetic nephropathy mouse model. To reduce sulfation of HS specifically in the endothelium, we generated Ndst1 Tie2Cre mice in which N-deacetylase/N-sulfotransferase-1 (Ndst1), the gene that initiates HS sulfation modifications in HS biosynthesis, was expressly ablated in endothelium. To induce diabetes, age-matched male Ndst1 Tie2Cre (wild type) and Ndst1 Tie2Cre mice on a C57Bl/6J background were injected intraperitoneally with streptozotocin (STZ) (50 mg/kg) on five consecutive days (N = 10-11/group). Urine and plasma were collected. Four weeks after diabetes induction the animals were sacrificed and kidneys were analyzed by immunohistochemistry and qRT-PCR. Compared to healthy controls, diabetic Ndst1 Tie2Cre mice showed increased glomerular macrophage infiltration, mannose binding lectin complement deposition and glomerulosclerosis, whereas these pathological reactions were prevented significantly in the diabetic Ndst1 Tie2Cre animals (all three p < 0.01). In addition, the expression of the podocyte damage marker desmin was significantly higher in the Ndst1 Tie2Cre group compared to the Ndst1 Tie2Cre animals (p < 0.001), although both groups had comparable numbers of podocytes. In the cortical tubulo-interstitium, similar analyses show decreased interstitial macrophage accumulation in the diabetic Ndst1 Tie2Cre animals compared to the diabetic Ndst1 Tie2Cre mice (p < 0.05). Diabetic Ndst1 Tie2Cre animals also showed reduced interstitial fibrosis as evidenced by reduced density of αSMA-positive myofibroblasts (p < 0.01), diminished collagen III deposition (p < 0.001) and reduced mRNA expression of collagen I (p < 0.001) and fibronectin (p < 0.001). Our studies indicate a pivotal role of endothelial HS in the development of renal inflammation and fibrosis in diabetic nephropathy in mice. These results suggest that HS is a possible target for therapy in diabetic nephropathy.
Chemerin/ChemR23 axis promotes inflammation of glomerular endothelial cells in diabetic nephropathy.
Shang Jin,Wang Luyao,Zhang Ya,Zhang Shiyi,Ning Lina,Zhao Jifang,Cheng Genyang,Liu Dong,Xiao Jing,Zhao Zhanzheng
Journal of cellular and molecular medicine
Diabetic nephropathy (DN) is characterized by inflammation of renal tissue. Glomerular endothelial cells (GEnCs) play an important role in inflammation and protein leakage in urine in DN patients. Chemerin and its receptor ChemR23 are inducers of inflammation. The aim of this study was to investigate the function of chemerin/ChemR23 in GEnCs of DN patients. Immunohistochemical staining and qRT-PCR were used to measure the expression of chemerin, ChemR23 and inflammatory factors in renal tissues of DN patients. Db/db mice were used as animal model. ChemR23 of DN mice was knocked down by injecting LV3-shRNA into tail vein. Inflammation, physiological and pathological changes in each group was measured. GEnCs were cultured as an in vitro model to study potential signalling pathways. Results showed that expression of chemerin, ChemR23 and inflammatory factors increased in DN patients and mice. LV3-shRNA alleviated renal damage and inflammation in DN mice. GEnCs stimulated by glucose showed increased chemerin, ChemR23 and inflammatory factors and decreased endothelial marker CD31. Both LV3-shRNA and SB203580 (p38 MAPK inhibitor) attenuated chemerin-induced inflammation and injury in GEnCs. Taken together, chemerin/ChemR23 axis played an important role in endothelial injury and inflammation in DN via the p38 MAPK signalling pathway. Suppression of ChemR23 alleviated DN damage.
Zingerone attenuates diabetic nephropathy through inhibition of nicotinamide adenine dinucleotide phosphate oxidase 4.
Cui Yan,Shi Yan,Bao Yan,Wang Shulong,Hua Qiuju,Liu Yun
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
Diabetes affects a large proportion of population wide across the world and kidney is a main target organ of diabetic complications. Zingerone is a stable active component derived from dry ginger rhizome. We investigated the effect of zingerone on diabetic nephropathy and explored the possible mechanisms. We showed that zingerone decreased the levels of serum insulin, C-peptide and glycosylated hemoglobin A1c. The levels of blood urea nitrogen (BUN), serum creatinine, urinary albumin content and albumin/creatinine ratio (ACR) were reduced by zingerone. Moreover, zingerone attenuated the pathological injuries of kidneys, reduced the surface area of Bowman's capsule, Bowman's space, glomerular tuft, and decreased the expression of collagen IV and fibronectin in kidneys in db/db mice. The high levels of triglyceride and cholesterol, and high expression of TNFɑ and IL-6 were decreased by zingerone. Furthermore, zingerone decreased the level of MDA and increased the content of glutathione (GSH). NADPH oxidase 4 (NOX4) expression was significantly increased in kidneys of db/db mice and in HK-2 cells after exposure to high glucose. Zingerone significantly decreased the expression of NOX4 in vivo and in vitro. Upregualtion of NOX4 significantly inhibited zingerone-induced protective effects against the cytotoxicity of high glucose. Downregulation of NOX4 was responsible for zingerone-exhibited pharmacological activities and reduction of diabetic nephropathy. Overall, zingerone is a promising therapeutic treatment to attenuate diabetic nephropathy.
Cyanidin-3-O-glucoside ameliorates diabetic nephropathy through regulation of glutathione pool.
Qin Yan,Zhai Qianqian,Li Yan,Cao Meng,Xu Yun,Zhao Kelei,Wang Tao
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
Diabetic nephropathy (DN) is a common complication of diabetes and the major cause of chronic kidney disease. Cyanidin 3-glucoside (C3G) is the most widespread anthocyanin in nature. In the present study, we aimed to investigate the possible effects of C3G on DN in db/db mice. We found that body weights and high levels of fasting blood glucose, serum insulin, C-peptide, glycosylated hemoglobin A1c, and systolic blood pressure in diabetic mice were significantly reduced by C3G. C3G also reduced the ratio of kidney to body weight and the levels of blood urea nitrogen (BUN), serum creatinine, urinary albumin content and albumin/creatinine ratio (ACR), ameliorated the pathological changes of kidneys, reduced the surface area of Bowman's capsule, glomerular tuft, Bowman's space, and decreased renal expression of collagen IV, fibronectin, transforming growth factor β 1 (TGFβ1), matrix metalloprotein 9 (MMP9) and α-smooth muscle actin (α-SMA) in db/db mice. The Lee's index, perirenal white adipose tissue weight, and high levels of blood and renal triglyceride and cholesterol were decreased by C3G. Moreover, C3G reduced systemic levels and renal expression of tumor necrosis factor ɑ (TNFɑ), IL-1ɑ, and monocyte chemotactic protein-1 (MCP-1), indicating the inhibition of inflammation. Furthermore, C3G increased glutathione (GSH) level and decreased GSSG level in kidneys of diabetic mice. The renal mRNA expression of glutamate-cysteine ligase catalytic subunit (GCLC) and glutamate-cysteine ligase modifier subunit (GCLM) was increased by C3G in diabetic mice. Buthionine sulphoximine (BSO), an inhibitor of GSH synthesis, inhibited the effects of C3G on glucose metabolic dysfunction and DN. The data demonstrates that enhancement of GSH pool is involved in the renal-protective effects of C3G. Overall, C3G could be a promising therapeutic option for attenuation of diabetes and DN.
SP600125 suppresses expression and results in NRF2-mediated prevention of diabetic nephropathy.
Zhang Huan,Liu Xiuxia,Zhou Shanshan,Jia Ye,Li Ying,Song Yuguo,Wang Junnan,Wu Hao
Journal of molecular endocrinology
c-Jun N-terminal kinase (JNK) contributes to the pathogenesis of diabetic nephropathy (DN). The JNK inhibitor SP600125 was reported to ameliorate DN. However, the mechanism remained unclear. We previously reported that SP600125 activated nuclear factor erythroid 2-related factor 2 (NRF2), a governor of the cellular antioxidant defense system, in the aortas of the diabetic mice. Given the critical role of NRF2 in preventing DN, the present study aimed to test whether or not NRF2 is required for SP600125's protection against DN. To test the role of NRF2 in SP600125's effect, streptozotocin-induced C57BL/6 wild-type (WT) and -knockout (KO) diabetic mice were treated in the presence or absence of SP600125, for 24 weeks. To explore the mechanism by which SP600125 activates NRF2, mouse mesangial cells (MMCs) were treated with high glucose (HG), in the presence or absence of either SP600125 or JNK siRNA. SP600125 significantly attenuated the diabetes-induced renal oxidative stress, inflammation, fibrosis, pathological change and dysfunction in the WT, but not the KO mice. SP600125 inactivated JNK, inhibited kelch-like ECH-associated protein 1 expression, preserved NRF2 protein and facilitated its nuclear translocation in the kidneys of the WT mice, the effects of which were similarly produced by either SP600125 or JNK siRNA in HG-treated MMCs. Further, both SP600125 and JNK siRNA alleviated HG-induced mesangial oxidative stress and expression of inflammatory and fibrotic genes. The present study demonstrates that NRF2 is required for SP600125's protection against DN. SP600125 activates NRF2 possibly via inhibition of JNK-induced expression.
miR-485 suppresses inflammation and proliferation of mesangial cells in an in vitro model of diabetic nephropathy by targeting NOX5.
Wu Jian,Lu Kan,Zhu Mingying,Xie Xin,Ding Yaqin,Shao Xiaohong,Chen Yiyue,Liu Jibo,Xu Mengzhu,Xu Yi,Zhou Jing,Shen Xiaoyu,Zhu Chunling
Biochemical and biophysical research communications
Diabetic nephropathy (DN) is among the common complications of diabetes and is a major cause of end-stage kidney disease. Emerging data indicate that renal inflammation is involved in DN progression and aggravation. Still, the exact cellular mechanisms remain unclear. Dysregulated expression of microRNAs (miRNAs) is associated with multiple diseases, including DN. The relationship between miRNAs and inflammation in DN is also unexplored. Here, we evaluated the role of miR-485 in mediating the response of human mesangial cells (HMCs) to a high glucose (HG) concentration, and the potential underlying mechanism. We found that miR-485 expression is significantly decreased in HG-stimulated HMCs. Overexpression of miR-485 suppressed HG-induced proliferation of HMCs. Lower production of proinflammatory cytokines (i.e., TNF-α, IL-1β, and IL-6) was observed in miR-485-overexpressing HMCs. Overexpression of miR-485 markedly suppressed the overexpression of extracellular-matrix proteins, e.g., collagen IV (Col IV) and fibronectin (FN), in HG-stimulated HMCs. Furthermore, miR-485 suppressed the expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 5 (NOX5), restrained the HG-induced HMC proliferation, downregulated the expression of proinflammatory cytokines, and inhibited the production of extracellular-matrix proteins in HMCs. These results provide new insights into the involvement of the miR-485-NOX5 signaling pathway in DN progression.
Immunomodulatory Effects of the Nutraceutical Garlic Derivative Allicin in the Progression of Diabetic Nephropathy.
Arellano Buendía Abraham Said,Tostado González Montserrat,Sánchez Reyes Omegar,García Arroyo Fernando Enrique,Argüello García Raúl,Tapia Edilia,Sánchez Lozada Laura Gabriela,Osorio Alonso Horacio
International journal of molecular sciences
Diabetic nephropathy (DN) is presently the primary cause of chronic kidney disease and end-stage renal disease (ESRD). It has been suggested that inflammation and oxidative stress, in addition to or in concert with the metabolic changes, plays an important role in the maintenance and progression of the disease. Therefore, attenuating or blocking these mechanisms may be a therapeutic target to delay the progression of the disease. Diallyl thiosulfinate (allicin), a compound derived from garlic, inhibits free radical formation, increases glutathione synthesis and decreases the levels of proinflammatory molecules in vitro. This research aimed to assess the effect of allicin on oxidative stress and inflammation-induced diabetes. Animals were divided into control and diabetes (streptozotocin 50 mg/kg i.p.), and maintained for 30 days. After 30 days, the group of diabetic animals was subdivided into diabetes and allicin-treated diabetes (16 mg/kg/day oral gavage). The three experimental groups were maintained for another month. We analyzed the status of renal function, oxidative stress and proinflammatory cytokines. The untreated diabetic group showed hyperglycemia and increased diuresis, creatinine clearance, proteinuria, glycosuria and urinary excretion of -acetyl-β-d-glucosaminidase (NAG), as well as increased oxidative stress and the expression of interleukin 1β (IL-1β), IL-6, nuclear factor kappa beta (NFκβ) and transforming growth factor-β1 (TGF-β1) in plasma and kidney. In contrast, the inhibitor of NFκβ (Iκβ) is decreased in the cortex. It has been demonstrated that the allicin treatment decreases hyperglycemia, polyuria, and NAG excretion. The oxidative stress and proinflammatory cytokines were also reduced by the allicin treatment. In conclusion, allicin delays the progression of diabetic nephropathy through antioxidant and anti-inflammatory mechanisms.
Long noncoding RNA NONHSAG053901 promotes diabetic nephropathy via stimulating Egr-1/TGF-β-mediated renal inflammation.
Peng Wenfang,Huang Shan,Shen Lisha,Tang Yubing,Li Huihua,Shi Yongquan
Journal of cellular physiology
Diabetic nephropathy (DN) is an important factor leading to end-stage kidney disease that affects diabetes mellitus patients globally. Our previous transcriptome sequencing has identified a large group of differentially expressed long noncoding RNA (lncRNA) in early development of DN. On basis of this, we aimed to investigate the function of lncRNA NONHSAG053901 in DN pathogenesis. In this study, we revealed that the expression of NONHSAG053901 was drastically elevated in both DN mouse model and mesangial cells (MCs). It was found that overexpression of NONHSAG053901 remarkably promoted inflammation, fibrosis and proliferation in MCs. Consistently, further investigations suggested that the stimulation of NONHSAG053901 on proinflammatory cytokines via direct binding to early growth response protein 1 (Egr-1). Interaction between Egr-1 and transforming growth factor β (TGF-β) could augment TGF-β function in DN inflammation. Furthermore, the effects of NONHSAG053901 on stimulation of proinflammatory cytokines were abolished by knockdown of Egr-1. These results together suggested that NONHSAG053901 promoted proinflammatory cytokines via stimulating Egr-1/TGF-β mediated renal inflammation.
Down-regulation of microRNA-21 reduces inflammation and podocyte apoptosis in diabetic nephropathy by relieving the repression of TIMP3 expression.
Chen Xiaoping,Zhao Lei,Xing Yanwei,Lin Bo
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
BACKGROUND:Several miRNAs including miR-21 have emerged as important regulators in the development of diabetic nephropathy (DN). However, the molecular mechanism of miR-21 underlying DN pathogenesis remains to be further discussed. METHODS:Streptozotocin (STZ)-induced DN rats and high glucose (HG)-induced podocytes were used as the in vivo and in vitro models of DN. miR-21 level was detected by qRT-PCR assay. Inflammatory cytokine levels were assessed by ELISA. Kidney injury of rats was evaluated by blood glucose, serum creatinine and blood urine nitrogen concentrations and periodic acid schiff (PAS) staining. Apoptosis in kidney tissues and podocytes was determined by TUNEL and flow cytometry analyses, respectively. Western blot analysis was applied to measure the protein levels of tissue inhibitors of metalloproteinase 3 (TIMP3), Bax and Bcl-2. The relationship between TIMP3 and miR-21 was confirmed by luciferase reporter assay. RESULTS:miR-21 expression was upregulated in serum and kidney tissues of DN patients, kidney tissues of STZ-induced DN rats, and HG-treated podocytes. miR-21 depletion inhibited pro-inflammatory factor (IL-1β, TNF-α) secretions and alleviated kidney damages in STZ-induced DN rats. Moreover, TIMP3 was a target of miR-21 in HG-treated podocytes. Additionally, TIMP3 overexpression abated HG-induced inflammatory responses and podocyte apoptosis. Furthermore, the inhibitory effects of TIMP3 on inflammatory responses and podocyte apoptosis were alleviated by increased miR-21. CONCLUSION:The down-regulation of miR-21 inhibited the progression of DN by targeting TIMP3 in STZ-induced DN rats and HG-treated podocytes, elucidating a novel regulatory mechanism of miR-21 in DN progression and offering a potential target for DN therapy.
Small Molecule Inhibiting Nuclear Factor-kB Ameliorates Oxidative Stress and Suppresses Renal Inflammation in Early Stage of Alloxan-Induced Diabetic Nephropathy in Rat.
Borgohain Manash P,Lahkar Mangala,Ahmed Sahabuddin,Chowdhury Liakat,Kumar Saurabh,Pant Rajat,Choubey Abhinav
Basic & clinical pharmacology & toxicology
Diabetic nephropathy is one of the major microvascular complications of diabetes mellitus which ultimately gives rise to cardiovascular diseases. Prolonged hyperglycaemia and chronic renal inflammation are the two key players in the development and progression of diabetic nephropathy. Nuclear factor kB (NF-kB)-mediated inflammatory cascade is a strong contributor to the renovascular inflammation in diabetic nephropathy. Here, we studied the effects of piceatannol, a potent NF-kB inhibitor, on various oxidative stress markers and NF-kB dependent diabetic renoinflammatory cascades in rat induced by alloxan (ALX). Experimental diabetes was induced in male Wistar rats by a single intraperitoneal dose, 150 mg/kg body-weight (b.w.) of ALX. Diabetic rats were treated with Piceatannol (PCTNL) at a dose of 30 and 50 mg/kg b.w. After 14 days of oral treatment, PCTNL significantly restored blood sugar level, glomerular filtration rate, serum markers and plasma lipids. PCTNL administration also reversed the declined activity of cellular antioxidant machineries namely superoxide dismutase and glutathione and the elevated levels of malondialdehyde and nitric oxide. Moreover, piceatannol-treated groups showed marked inhibition of renal pro-inflammatory cytokines and NF-kB p65/p50 binding to DNA. Renal histopathological investigations also supported its ameliorative effects against diabetic kidney damage. Importantly, effects were more prominent at a dose of 50 mg/kg, and in terms of body-weight gain, PCTNL failed to effect significantly. However, overall findings clearly demonstrated that PCTNL provides remarkable renoprotection in diabetes by abrogating oxidative stress and NF-kB activation - and might be helpful in early stage of diabetic nephropathy.
Rhinacanthins-rich extract and rhinacanthin C ameliorate oxidative stress and inflammation in streptozotocin-nicotinamide-induced diabetic nephropathy.
Zhao Ling-Ling,Makinde Emmanuel Ayobami,Shah Muhammad Ajmal,Olatunji Opeyemi Joshua,Panichayupakaranant Pharkphoom
Journal of food biochemistry
In this present study, rhinacanthins-rich extract (RRE) and rhinacanthin C (RC) the main bioactive constituent of Rhinacanthus nasutus was investigated for their protective effect against diabetic nephropathy (DN). Diabetes was induced by administering nicotinamide (100 mg/kg, i.p.)/streptozotocin (60 mg/kg, i.p.) and diabetic rats were orally administered with RRE and RC for 4 weeks. RRE and RC significantly reduced the kidney index, renal oxidative stress markers, and pro-inflammatory cytokines. Furthermore, RRE and RC increased renal levels of glutathione, superoxide dismutase, catalase, and attenuated diabetic induced renal damages. In conclusion, RRE and RC confer protective effect against DN through the inhibition of oxidative stress and inflammation and could be a potential medicinal or nutritional supplement for the prevention of DN. PRACTICAL APPLICATIONS: Rhinacanthus nasutus is a medicinal plant that is extensively used in Thai traditional medicine as an antibacterial, antifungal, antidiabetic, and anti-inflammatory agent. The plant is rich in naphthoquinones, which confer it with several excellent bioactivities. The rich extract of the leaves was prepared with three major bioactive components and the extract was evaluated for its renoprotective effect in diabetic rats. The results from this study provides valuable pharmacological information that supports the use of the plant, especially the rich extract in the prevention and treatment of diabetes and diabetic complications.
AGE-RAGE axis blockade in diabetic nephropathy: Current status and future directions.
Sanajou Davoud,Ghorbani Haghjo Amir,Argani Hassan,Aslani Somayeh
European journal of pharmacology
Diabetic nephropathy is one of the most frequent micro-vascular complications both in type 1 and type 2 diabetic patients and is the leading cause of end-stage renal disease worldwide. Although disparate mechanisms give rise to the development of diabetic nephropathy, prevailing evidence accentuates that hyperglycemia-associated generation of advanced glycation end products (AGEs) plays a central role in the disease pathophysiology. Engagement of the receptor for AGE (RAGE) with its ligands provokes oxidative stress and chronic inflammation in renal tissues, ending up with losses in kidney function. Moreover, RAGE activation evokes the activation of different intracellular signaling pathways like PI3K/Akt, MAPK/ERK, and NF-κB; and therefore, its blockade seems to be an attractive therapeutic target in these group of patients. By recognizing the contribution of AGE-RAGE axis to the pathogenesis of diabetic nephropathy, agents that block AGEs formation have been at the heart of investigations for several years, yielding encouraging improvements in experimental models of diabetic nephropathy. Even so, recent studies have evaluated the effects of specific RAGE inhibition with FPS-ZM1 and RAGE-aptamers as novel therapeutic strategies. Despite all these promising outcomes in experimental models of diabetic nephropathy, no thorough clinical trial have ever examined the end results of AGE-RAGE axis blockade in patients of diabetic nephropathy. As most of the AGE lowering or RAGE inhibiting compounds have emerged to be non-toxic, devising novel clinical trials appears to be inevitable. Here, the current potential treatment options for diabetic nephropathy by AGE-RAGE inhibitory modalities have been reviewed.
Allium tuberosum alleviates diabetic nephropathy by supressing hyperglycemia-induced oxidative stress and inﬂammation in high fat diet/streptozotocin treated rats.
Ni Ziyuan,Guo Lihua,Liu Feng,Olatunji Opeyemi Joshua,Yin Min
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
The objective of this study was to evaluate the effect of the butanol fraction from Allium tuberosum (BFAT) in high fat diet/streptozotocin (HFD/STZ) induced diabetic nephropathy. Wistar rats were fed with HFD for 4 weeks and thereafter administered with 35 mg/kg STZ intraperitoneally. Diabetic rats were treated with BFAT (100 or 400 mg/kg) and metformin (150 mg/kg) for 40 days. After treatment, the blood, urine and kidney tissues were obtained for biochemical and histological analysis. BFAT markedly decreased blood glucose, serum creatinine, blood urea nitrogen and urinary albumin levels in diabetic rats. Furthermore, BFAT upregulated renal antioxidant enzymes status (glutathione, superoxide dismutase and catalase) and decreased lipid peroxidation product in diabetic rats as well as reduced the levels of renal pro-inflammatory cytokines in diabetic rats. In addition, BFAT significantly decreased serum and renal levels of triglyceride and cholesterol in the treated diabetic rats. These results revealed that A. tuberosum possesses attenuative effects against diabetic nephropathy.
ADMA elevation does not exacerbate development of diabetic nephropathy in mice with streptozotocin-induced diabetes mellitus.
Rodionov Roman N,Jarzebska Natalia,Schneider Alfred,Rexin Annett,Sradnick Jan,Brilloff Silke,Martens-Lobenhoffer Jens,Bode-Böger Stefanie M,Todorov Vladimir,Hugo Christian,Weiss Norbert,Hohenstein Bernd
BACKGROUND AND AIMS:Cardiovascular disease is nowadays the major cause of mortality and morbidity worldwide. The risk of developing cardiovascular disease is significantly increased in patients with diabetic nephropathy. It has been suggested that asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO synthases (NOS), may play an important role in the pathogenesis of diabetic nephropathy. ADMA is mainly metabolized by dimethylarginine dimethylaminohydrolase 1 (DDAH1). The goal of this study was to test the hypothesis that elevation of systemic ADMA levels by knocking out DDAH1 would exacerbate functional and structural glomerular abnormalities in a murine model of diabetic nephropathy. METHODS:Streptozotocin (STZ) was used to induce diabetes in adult DDAH1 knock-out and wild type mice. Healthy mice served as controls. Mice were sacrificed after 20 weeks of diabetes. Plasma ADMA levels were assessed by isotope-dilution tandem mass spectrometry and albumin by ELISA. Kidneys were used for FACS analysis and were also stained for markers of inflammation, cell proliferation, glomerular cells and cell matrix. RESULTS:STZ led to development of diabetes mellitus in all injected animals. Deficiency of DDAH1 led to a significant increase in plasma ADMA levels in healthy and diabetic mice. The diabetic state itself did not influence systemic ADMA levels. Diabetic mice of both genotypes developed albuminuria and had increased glomerulosclerosis index. There were no changes in desmin expression, glomerular cell proliferation rate, matrix expansion and expression of Mac-2 antigen in the diabetic mice of both genotypes as compared to the healthy ones. CONCLUSIONS:In summary, STZ-induced diabetes led to the development of early features of diabetic nephropathy. Deficiency of DDAH1 and subsequent increase in systemic ADMA levels did not exacerbate these changes, indicating that ADMA is not the major mediator of diabetic nephropathy in this experiment model.
Improves Glomerular Fibrosis and Renal Dysfunction in Diabetic Nephropathy Model.
Yoon Jung Joo,Park Ji Hun,Kim Hye Jin,Jin Hong-Guang,Kim Hye Yoom,Ahn You Mee,Kim Youn Chul,Lee Ho Sub,Lee Yun Jung,Kang Dae Gill
Glomerular fibrosis is caused by an accumulation of intercellular spaces containing mesangial matrix proteins through either diffused or nodular changes. has been used in traditional medicine as a diuretic, a contraceptive, and an anti-inflammatory agent. The aim of this study was to investigate the effects of -EtOAc soluble fraction (DS-EA) on glomerular fibrosis and renal dysfunction, which has been implicated in diabetic nephropathy in human renal mesangial cells and db/db mice. DS-EA was administered to db/db mice at 10 or 50 mg/kg/day for 8 weeks. DS-EA treatment significantly ameliorated blood glucose, insulin, the homeostasis model assessment of insulin resistance (HOMA-IR) index, and HbA1c in diabetic mice. DS-EA decreased albumin excretion, creatinine clearance (Ccr), and plasma creatinine levels. DS-EA also ameliorated the levels of kidney injury molecules-1 (KIM-1) and C-reactive protein. DS-EA reduced the periodic acid-Schiff (PAS) staining intensity and basement membrane thickening in glomeruli of the diabetic nephropathy model. In addition, DS-EA suppressed transforming growth factor-β (TGF-β)/Smad signaling. Collagen type IV, a glomerular fibrosis biomarker, was significantly decreased upon DS-EA administration. DS-EA pretreatment attenuated levels of inflammation factors such as intracellular cell adhesion molecule-1 (ICAM-1) and monocyte chemoattractant protein-1 (MCP-1). DS-EA inhibited the translocation of nuclear factor kappa B (NF-κB) in Angiotensin II (Ang II)-stimulated mesangial cells. These findings suggest that DS-EA has a protective effect against renal inflammation and fibrosis. Therefore, DS-EA may serve as a potential therapeutic agent targeting glomerulonephritis and glomerulosclerosis, which lead to diabetic nephropathy.
CXCL16 deficiency attenuates diabetic nephropathy through decreasing oxidative stress and inflammation.
Ye Yanna,Chen Qingzhen,Li Jinmeng,Jin Leigang,Zheng Jujia,Li Xiaokun,Lin Zhuofeng,Gong Fanghua
Biochemical and biophysical research communications
Soluble C-X-C chemokine ligand 16 (CXCL16) is related to the inflammatory response in liver injury and involved in the pathogenesis of renal dysfunction in diabetes patients. However, the exact role of elevated CXCL16 in diabetic nephropathy (DN) remains unclear. In this study, we investigated the role of CXCL16 in streptozcin (STZ)-induced diabetic nephropathy (DN) in mice. The results showed that fasting blood glucose (FBG) and 24 h urinary protein, triglyceride, and cholesterol levels increased in diabetic mice, and these changes were partially ameliorated in CXCL16 KO mice. Meanwhile, the results also showed that ROS generation was suppressed and the expression levels of inflammatory factors and infiltration factors were inhibited both in vivo and in vitro using DN models. In addition, the total AKT protein and p-AKT levels were decreased in CXCL16-depleted HK-2 cells that were treated with LPS. These findings suggest that the CXCL16 gene product promotes inflammatory factors and cell infiltration factors, and inhibits the expression of antioxidant factors to accelerate the development of DN, and CXCL16 deficiency attenuates DN may be involved in the AKT signaling pathway.
Increased TRPC6 expression is associated with tubular epithelial cell proliferation and inflammation in diabetic nephropathy.
Fu Yanqin,Wang Chongxian,Zhang Dongming,Xin Yaping,Li Jun,Zhang Yuanyuan,Chu Xiaojing
Although TRPC6 expression is shown to be significantly elevated in a rat model diabetic nephropathy (DN), its expression and role in human DN are unclear. We thus explored the role of TRPC6 in the pathophysiology of tubular epithelial cell injury following DN. HK-2 cells were cultured in a high-glucose medium to induce a DN cell model. Ad-TRPC6 and TRP6 siRNA were transfected to overexpress and knock down TRPC6. We found that TRPC6 expression was significantly upregulated in DN tissues and cells. TRPC6 siRNA inhibited cell proliferation and promoted cell apoptosis in HK-2 cells treated with high glucose, whereas Ad-TRPC6 showed the opposite effect. Furthermore, Ad-TRPC6 significantly promoted release of IL-8 and IL-6. Subsequent experiments demonstrated that the signaling pathway of nuclear factor of activated T cells (NFAT) was activated by Ad-TRPC6 and deactivated by TRPC6 siRNA. The NFAT signaling inhibitor, FK-506, eliminated the effect of TRPC6 on HK-2 cells. These results suggest that TRPC6 was upregulated in DN and could promote cell proliferation and inflammation by inhibiting the NFAT signaling pathway in tubular epithelial cells.
Brazilin Ameliorates Diabetic Nephropathy and Inflammation in db/db Mice.
Li Zhan-Yuan,Zheng Yu,Chen Yan,Pan Min,Zheng Shu-Bei,Huang Wen,Zhou Zhi-Hong,Ye Han-Yang
Hyperglycemia and inflammation play important roles in the pathogenesis of diabetic nephropathy (DN). Brazilin might be an effective pharmacological agent against hyperglycemia and inflammation. In our present study, we explored whether brazilin mitigated pathological progression, inflammation, and extracellular matrix (ECM) accumulation in a mouse model of diabetic nephropathy. Brazilin reduced aggravated biochemical indices of DN (proteinuria and the serum glucose level) and renal hypertrophy. Brazilin also improved renal morphology and inhibited macrophage infiltration, as manifested by different pathological staining methods. Brazilin reduced the levels of pro-inflammatory cytokines and CD68, a macrophage marker, in the kidney cortex, as revealed by both RT-PCR and western blotting experiments. Furthermore, brazilin significantly downregulated the serum levels of pro-inflammatory cytokines and chemokines. Interestingly, brazilin significantly upregulated the levels of the anti-inflammatory factor IL-10, and prevented ECM accumulation. Brazilin reduced nuclear translocation of the NF-κB p65 subunit both in vitro and in vivo. Thus, brazilin might be a useful treatment for DN, through mitigating hypoglycemia, inflammation, and ECM accumulation.
FGF23 improves diabetic nephropathy by attenuating renal fibrosis and inflammation.
Zhang Xiaomin,Guo Kaiwen,Xia Feng,Zhao Xinyu,Huang Zhifeng,Niu Jianlou
BACKGROUND:High level of serum fibroblast growth factor 23 (FGF23) is implicated in the development and progression of diabetic nephropathy (DN), making it a crucial factor in the pathogenesis of DN. FGF23 is also tightly correlated with inflammation in the progression of DN. The aim of this study was to explore whether the C-terminal of FGF23 (FGF23), an antagonist that can block the FGF23 signaling pathway by competing with intact FGF23, could exhibit a therapeutic effect on DN. RESULTS:Biochemical data and histological examination showed that FGF23 administration ameliorated the functional and morphological abnormalities of db/db mice with DN without changing the levels of circulating FGF23 and phosphate. Evaluation of morphology and fibrosis by Masson's trichrome staining and IHC staining of fibronectin, PCR, and western blot analysis showed that FGF23 prevents diabetes-induced fibrosis in db/db mice. Importantly, FGF23 decreased the levels of inflammatory cytokines in serum and renal tissues. CONCLUSION:FGF23 may improve diabetic nephropathy by decreasing inflammation and fibrosis in db/db mice, suggesting that blocking of FGF23 action remains an important therapeutic target for the prevention or attenuation of the progression of DN.
SGLT2 Protein Expression Is Increased in Human Diabetic Nephropathy: SGLT2 PROTEIN INHIBITION DECREASES RENAL LIPID ACCUMULATION, INFLAMMATION, AND THE DEVELOPMENT OF NEPHROPATHY IN DIABETIC MICE.
Wang Xiaoxin X,Levi Jonathan,Luo Yuhuan,Myakala Komuraiah,Herman-Edelstein Michal,Qiu Liru,Wang Dong,Peng Yingqiong,Grenz Almut,Lucia Scott,Dobrinskikh Evgenia,D'Agati Vivette D,Koepsell Hermann,Kopp Jeffrey B,Rosenberg Avi Z,Levi Moshe
The Journal of biological chemistry
There is very limited human renal sodium gradient-dependent glucose transporter protein (SGLT2) mRNA and protein expression data reported in the literature. The first aim of this study was to determine SGLT2 mRNA and protein levels in human and animal models of diabetic nephropathy. We have found that the expression of SGLT2 mRNA and protein is increased in renal biopsies from human subjects with diabetic nephropathy. This is in contrast to db-db mice that had no changes in renal SGLT2 protein expression. Furthermore, the effect of SGLT2 inhibition on renal lipid content and inflammation is not known. The second aim of this study was to determine the potential mechanisms of beneficial effects of SGLT2 inhibition in the progression of diabetic renal disease. We treated db/db mice with a selective SGLT2 inhibitor JNJ 39933673. We found that SGLT2 inhibition caused marked decreases in systolic blood pressure, kidney weight/body weight ratio, urinary albumin, and urinary thiobarbituric acid-reacting substances. SGLT2 inhibition prevented renal lipid accumulation via inhibition of carbohydrate-responsive element-binding protein-β, pyruvate kinase L, SCD-1, and DGAT1, key transcriptional factors and enzymes that mediate fatty acid and triglyceride synthesis. SGLT2 inhibition also prevented inflammation via inhibition of CD68 macrophage accumulation and expression of p65, TLR4, MCP-1, and osteopontin. These effects were associated with reduced mesangial expansion, accumulation of the extracellular matrix proteins fibronectin and type IV collagen, and loss of podocyte markers WT1 and synaptopodin, as determined by immunofluorescence microscopy. In summary, our study showed that SGLT2 inhibition modulates renal lipid metabolism and inflammation and prevents the development of nephropathy in db/db mice.
Urinary mitochondrial DNA: A potential early biomarker of diabetic nephropathy.
Cao Hongdi,Wu Jining,Luo Jing,Chen Xiaolan,Yang Junwei,Fang Li
Diabetes/metabolism research and reviews
BACKGROUND:Mitochondrial dysfunction and chronic sterile inflammation are common features of type 2 diabetes. Therefore, we aimed to investigate whether mitochondrial DNA (mtDNA) could be a biomarker implicated in the progression of type 2 diabetes and diabetic nephropathy and explore the underlying mechanism. MATERIAL AND METHODS:We developed a method for relative quantification of mtDNA content in clinical practice. qRT-PCR was used to measure the mtDNA content both in vivo in CD-1 mice with diabetes induction by streptozotocin and in vitro in murine endothelial cells and conditionally immortalized mouse podocytes. By pumping mtDNA into the mouse circulation, the effect of mtDNA on the kidney was assessed in mice. In patients with type 2 diabetes (n = 42; 24 males; mean age 57.9 ± 12.00 years), plasma mtDNA was evaluated. RESULTS:Plasma mtDNA content was significantly decreased in patients with type 2 diabetes, particularly those with significant proteinuria. In vitro, high glucose treatment suppressed intracellular mtDNA content and facilitated the extracellular release of mtDNA, so excessive circulatory mtDNA induced by high glucose might be filtered through the kidney and then into urine. Indeed, urinary mtDNA content was significantly increased in both diabetic patients and mice. Moreover, by pumping excess mtDNA into circulation in mice, filtered mtDNA could trigger inflammation and induce kidney injury. CONCLUSION:Excessive mtDNA filtered through the kidney under diabetic conditions may be involved in chronic renal inflammation. Reduced plasma mtDNA content and increased urinary mtDNA/creatinine ratio might play a potential role as an early biomarker of diabetic nephropathy.
The Effects of Coenzyme Q10 Supplementation on Glucose Metabolism, Lipid Profiles, Inflammation, and Oxidative Stress in Patients With Diabetic Nephropathy: A Randomized, Double-Blind, Placebo-Controlled Trial.
Gholnari Tahereh,Aghadavod Esmat,Soleimani Alireza,Hamidi Gholam Ali,Sharifi Nasrin,Asemi Zatollah
Journal of the American College of Nutrition
OBJECTIVE:Data on the effects of coenzyme Q10 (CoQ10) supplementation on glucose metabolism, lipid profiles, inflammation, and oxidative stress in subjects with diabetic nephropathy (DN) are scarce. This research was done to determine the effects of CoQ10 supplementation on metabolic status in subjects with DN. METHODS:This randomized double-blind placebo-controlled clinical trial was done in 50 subjects with DN. Participants were randomly assigned into two groups to intake either 100 mg/day CoQ10 supplements (n = 25) or placebo (n = 25) for 12 weeks. Fasting blood samples were obtained at first and after 12-week intervention to quantify metabolic profiles. RESULTS:After 12 weeks of treatment, compared with the placebo, CoQ10 supplementation resulted in significant decreases in serum insulin levels (-3.4 ± 6.8 vs +0.8 ± 6.4 µIU/mL, p = 0.02), homeostasis model of assessment-estimated insulin resistance (-1.0 ± 2.0 vs +0.2 ± 1.8, p = 0.03), homeostasis model of assessment-estimated B cell function (-12.3 ± 26.3 vs +3.5 ± 23.1, p = 0.02) and HbA1c (-1.1 ± 1.0 vs -0.1 ± 0.2%, p < 0.001), and a significant improvement in quantitative insulin sensitivity check index (+0.009 ± 0.01 vs -0.006 ± 0.01, p = 0.01). In addition, CoQ10 supplementation significantly decreased plasma malondialdehyde (MDA) (-0.6 ± 0.5 vs +0.5 ± 1.0 µmol/L, p < 0.001) and advanced glycation end products levels (AGEs) (-316.4 ± 380.9 vs +318.6 ± 732.0 AU, p < 0.001) compared with the placebo. Supplementation with CoQ10had no significant impacts on fasting plasma glucose (FPG), lipid profiles, and matrix metalloproteinase-2 (MMP-2) compared with the placebo. CONCLUSIONS:Taken together, our study demonstrated that CoQ10 supplementation for 12 weeks among DN patients had favorable effects on glucose metabolism, MDA, and AGEs levels, but unchanged FPG, lipid profiles, and MMP-2 concentrations.
Andrographolide ameliorates diabetic nephropathy by attenuating hyperglycemia-mediated renal oxidative stress and inflammation via Akt/NF-κB pathway.
Ji Xiaoqian,Li Changzheng,Ou Yitao,Li Ning,Yuan Kai,Yang Guizhi,Chen Xiaoyan,Yang Zhicheng,Liu Bing,Cheung Wai W,Wang Lijing,Huang Ren,Lan Tian
Molecular and cellular endocrinology
Diabetic nephropathy (DN) is characterized by proliferation of mesangial cells, mesangial hypertrophy and extracellular matrix (ECM) accumulation. Our recent study found that andrographolide inhibited high glucose-induced mesangial cell proliferation and fibronectin expression through inhibition of AP-1 pathway. However, whether andrographolide has reno-protective roles in DN has not been fully elucidated. Here, we studied the pharmacological effects of andrographolide against the progression of DN and high glucose-induced mesangial dysfunction. Diabetes was induced in C57BL/6 mice by intraperitoneal injection of streptozotocin (STZ). After 1 weeks after STZ injection, normal diet was substituted with a high-fat diet (HFD). Diabetic mice were intraperitoneal injected with andrographolide (2 mg/kg, twice a week). After 8 weeks, functional and histological analyses were carried out. Parallel experiments uncovering the molecular mechanism by which andrographolide prevents from DN was performed in mesangial cells. Andrographolide inhibited the increases in fasting blood glucose, triglyceride, kidney/body weight ratio, blood urea nitrogen, serum creatinine and 24-h albuminuria in diabetic mice. Andrographolide also prevented renal hypertrophy and ECM accumulation. Furthermore, andrographolide markedly attenuated NOX1 expression, ROS production and pro-inflammatory cytokines as well. Additionally, andrographolide inhibited Akt/NF-κB signaling pathway. These results demonstrate that andrographolide is protective against the progression of experimental DN by inhibiting renal oxidative stress, inflammation and fibrosis.
NLRC5 deficiency ameliorates diabetic nephropathy through alleviating inflammation.
Luan Peipei,Zhuang Jianhui,Zou Jun,Li Hailing,Shuai Ping,Xu Xiaopeng,Zhao Yifan,Kou Wenxin,Ji Shuya,Peng Ai,Xu Yawei,Su Qing,Jian Weixia,Peng Wenhui
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
NOD-like receptor family caspase recruitment domain family domain containing 5 (NLRC5) has important roles in inflammation and innate immunity. NLRC5 was highly expressed in kidney from streptozotocin-induced diabetic mice, db/ db mice and patients with diabetes. Based on that evidence, the present study was designed to explore the roles of NLRC5 in the progression of diabetic nephropathy (DN). We examined kidney injury, including inflammation and fibrosis in Nlrc5 gene knockout ( Nlrc5) and wild-type (WT) diabetic mice. We found that Nlrc5 mice developed less-severe diabetic kidney injury compared with WT mice, exhibiting lower albuminuria, less fibronectin and collagen IV expression, and reduced macrophage infiltration but greater levels of podocin and nephrin in the diabetic kidney. The underlying mechanisms were further investigated in vitro with peritoneal macrophages and mesangial cells treated with high glucose. Reduced proinflammatory effect was observed in peritoneal macrophages from Nlrc5 mice, associated with NF-κB pathway suppression. Knocking down of NLRC5 in mesangial cells in high-glucose conditions was also associated with reduced NF-κB and TGF-β/Smad signaling. Taken together, NLRC5 promotes inflammation and fibrosis during DN progression partly through the effects on NF-κB and TGF-β/Smad pathways. NLRC5 may, therefore, be a promising therapeutic target for DN treatment.-Luan, P., Zhuang, J., Zou, J., Li, H., Shuai, P., Xu, X., Zhao, Y., Kou, W., Ji, S., Peng, A., Xu, Y., Su, Q., Jian, W., Peng, W. NLRC5 deficiency ameliorates diabetic nephropathy through alleviating inflammation.
The role of IL-18 in type 1 diabetic nephropathy: The problem and future treatment.
Elsherbiny Nehal M,Al-Gayyar Mohammed M H
Diabetic vascular complication is a leading cause of diabetic nephropathy, a progressive increase in urinary albumin excretion coupled with elevated blood pressure leading to declined glomerular filtration and eventually end stage renal failure. There is growing evidence that activated inflammation is contributing factor to the pathogenesis of diabetic nephropathy. Meanwhile, IL-18, a member of the IL-1 family of inflammatory cytokines, is involved in the development and progression of diabetic nephropathy. However, the benefits derived from the current therapeutics for diabetic nephropathy strategies still provide imperfect protection against renal progression. This imperfection points to the need for newer therapeutic agents that have potential to affect primary mechanisms contributing to the pathogenesis of diabetic nephropathy. Therefore, the recognition of IL-18 as significant pathogenic mediators in diabetic nephropathy leaves open the possibility of new potential therapeutic targets.
Ginger alleviates hyperglycemia-induced oxidative stress, inflammation and apoptosis and protects rats against diabetic nephropathy.
Al Hroob Amir M,Abukhalil Mohammad H,Alghonmeen Reham D,Mahmoud Ayman M
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
Oxidative stress plays a major role in the development and progression of diabetic nephropathy (DN). In this study, the potential protective effect of ginger (Zingiber officinale) rhizome extract on hyperglycemia-induced oxidative stress, inflammation and apoptosis was investigated. An experimental diabetic rat model was induced by intraperitoneal injection of streptozotocin. Diabetic rats were treated orally with 400 or 800 mg/kg/day Z. officinale extract for six weeks. Diabetic animals exhibited elevated blood glucose levels and glycated hemoglobin (HbA1c) with altered lipid profile. Blood urea nitrogen, serum creatinine and urea, and urine albumin levels were significantly increased in diabetic rats. Treatment with Z. officinale ameliorated hyperglycemia, hyperlipidemia and kidney function. In addition, Z. officinale minimized the histological alterations in the kidney of diabetic rats. Chronic hyperglycemia resulted in a significant increase in malondialdehyde, protein carbonyl, pro-inflammatory cytokines, cytochrome c and caspase-3 in the kidney of rats. Z. officinale extract significantly attenuated oxidative stress, inflammation and apoptosis, and enhanced antioxidant defenses in the diabetic kidney. In conclusion, this study strongly suggests that Z. officinale rhizome extract exerts a protective role against diabetes-induced renal injury by ameliorating oxidative stress, inflammation and apoptosis.
Diabetic nephropathy - is this an immune disorder?
Tesch Greg H
Clinical science (London, England : 1979)
Chronic diabetes is associated with metabolic and haemodynamic stresses which can facilitate modifications to DNA, proteins and lipids, induce cellular dysfunction and damage, and stimulate inflammatory and fibrotic responses which lead to various types of renal injury. Approximately 30-40% of patients with diabetes develop nephropathy and this renal injury normally progresses in about a third of patients. Due to the growing incidence of diabetes, diabetic nephropathy is now the main cause of end-stage renal disease (ESRD) worldwide. Accumulating evidence from experimental and clinical studies has demonstrated that renal inflammation plays a critical role in determining whether renal injury progresses during diabetes. However, the immune response associated with diabetic nephropathy is considerably different to that seen in autoimmune kidney diseases or in acute kidney injury arising from episodes of ischaemia or infection. This review evaluates the role of the immune system in the development of diabetic nephropathy, including the specific contributions of leucocyte subsets (macrophages, neutrophils, mast cells, T and B lymphocytes), danger-associated molecular patterns (DAMPs), inflammasomes, immunoglobulin and complement. It also examines factors which may influence the development of the immune response, including genetic factors and exposure to other kidney insults. In addition, this review discusses therapies which are currently under development for targeting the immune system in diabetic nephropathy and indicates those which have proceeded into clinical trials.
Zingerone (4-(4-hydroxy-3-methylphenyl)butan-2-one) ameliorates renal function via controlling oxidative burst and inflammation in experimental diabetic nephropathy.
Rehman Muneeb U,Rashid Shahzada Mudasir,Rasool Saiema,Shakeel Sheeba,Ahmad Bilal,Ahmad Sheikh Bilal,Madkhali Hassan,Ganaie Majid Ahmad,Majid Sabiya,Bhat Showkat Ahmad
Archives of physiology and biochemistry
Development of diabetic nephropathy (DN) is directly linked to oxidative stress and inflammation. In this context, inflammatory and oxidative markers have gained much attention as targets for therapeutic intervention. We studied the effect of zingerone in a streptozotocin/high fat diet (STZ/HFD)-induced type 2 diabetic Wistar rat model. Zingerone also known as vanillyl acetone is a pharmacologically active compound present usually in dry ginger. STZ/HFD caused excessive increase in ROS and inflammation in experimental animals. The treatment with zingerone markedly abrogated ROS levels, inhibited the NF-кB activation and considerably reduced level of other downstream inflammatory molecules (TNF-α, IL-6, IL-1β), furthermore, zingerone treatment improved renal functioning by significantly decreasing the levels of kidney toxicity markers KIM-1, BUN, creatinine, and LDH and suppressed TGF-β. Collectively, these findings indicate that zingerone treatment improved renal function by anti-hyperglycaemic, anti-oxidant, and anti-inflammatory effects, suggesting the efficacy of zingerone in the treatment of DN.
Targeting inflammation in diabetic nephropathy: a tale of hope.
Moreno Juan Antonio,Gomez-Guerrero Carmen,Mas Sebastian,Sanz Ana Belen,Lorenzo Oscar,Ruiz-Ortega Marta,Opazo Lucas,Mezzano Sergio,Egido Jesus
Expert opinion on investigational drugs
INTRODUCTION:Diabetic nephropathy (DN) is the leading cause of chronic kidney disease (CKD) and end-stage renal disease (ESRD). Beyond the new anti-diabetic drugs that possess markedly cardiovascular and renal protective effects, no novel direct therapies for DN have become available on the market in the last twenty years. Recently well-designed clinical trials for the treatment of DN, with attractive pathogenetic rationale, e.g. bardoxolone and atrasentan, were canceled or stopped because of safety concerns or lack of reaching the end points, respectively. AREAS COVERED:In this review, we focus on the involvement of inflammation in the pathogenesis of DN. We update information from recent experimental and clinical studies that reported beneficial effects of several agents targeting chemokines, cytokines, transcription factors and kinases as well as several compounds with anti-inflammatory properties on DN. EXPERT OPINION:Inflammation plays a key role in the DN progression. Preclinical studies have identified several anti-inflammatory molecules that effective decrease albuminuria and/or proteinuria. However, limited clinical trials in humans have been performed to confirm these results. Inhibitors of CCL2/CCR2, IL-1β and JAK/STAT pathways, and Nrf2 inducers are promising therapeutic options to improve the renal outcome of patients with DN, but appropriate clinical trials are necessary.
Umbelliferone ameliorates renal function in diabetic nephropathy rats through regulating inflammation and TLR/NF-κB pathway.
Wang Han-Qing,Wang Sha-Sha,Chiufai Kuok,Wang Qi,Cheng Xiao-Lan
Chinese journal of natural medicines
Diabetic nephropathy (DN) is a leading cause of renal failure, contributing to severe morbidity and mortality in diabetic patients. Umbelliferae (Umb) has been well characterized to exert protective effects in diabetes. However, the action and mechanism of Umb in DN remains unclear. In this work, we studied the effect of Umb in a streptozotocin (STZ)-induced DN rat model and explore its underlying mechanism. DN rats were treated withUmb (20, 40 mg·kg) orirbesartan (15 mg·kg) for 4 weeks. Levels of serum glucose, insulin, blood uric acid, creatinine, triglycerides (TG) and total cholesterol (TC) were measured bycommercial assay kits, respectively. Histopathological changes andinflammatory cytokine levels including IL-6, IL-1β and TNF-α in the kidney were also evaluated. Alterations in the expression of podocin, CD2AP and TLR/NF-κB were assessed by western blotting. Our results showed that Umb reduced renal injury in DN rat model, as evidenced by the decrease in blood glucose, 24 h urinary protein, serum creatinine, and blood uric acid. Umb also significantly ameliorated the renal histopathological alteration, and down-regulated the expression of epithelial-to-mesenchymal transition-related molecular markers podocin and CD2AP. Moreover, Umb inhibited TLR2, TLR4, MyD88 expressions, NF-κB activation and considerably reduced levels of other downstream inflammatory molecules (TNF-α, IL-6, IL-1β). These findings indicated that Umb improved renal function through regulating inflammation and TLR/NF-κB pathway, suggesting the potential efficacy of Umb in DN treatment.
Mapping Txnip: Key connexions in progression of diabetic nephropathy.
Kumar Anil,Mittal Ruchika
Pharmacological reports : PR
Studies demonstrates the major involvement of inflammatory and apoptotic pathway in the pathophysiology of diabetic nephropathy. The cross talk between inflammatory and apoptotic pathway suggests Txnip as a molecular connexion in progression of disease state. Txnip modulates inflammatory pathway (via ROS production and NLRP3 inflammasome activity) and apoptotic pathway (via mTOR pathway). The key contribution of Txnip in both the pathways, reflects, its crucial role in diabetic nephropathy. In the present review, we have first provided an overview of diabetic nephropathy and Txnip system, followed by the mechanistic insight of Txnip in the progression of diabetic nephropathy. This new mechanistic approach suggests to explore Txnip modulators as a promising therapeutic drug target in diabetic nephropathy.
Schisandrin B alleviates diabetic nephropathy through suppressing excessive inflammation and oxidative stress.
Mou Zhenxin,Feng Zhiguo,Xu Zheng,Zhuang Fei,Zheng Xuyong,Li Xiaokun,Qian Jianchang,Liang Guang
Biochemical and biophysical research communications
Diabetic nephropathy (DN) is a progressive kidney disease due to glomerular capillary damage in diabetic patients, with inflammation and oxidative stress implicated as crucial pathogenic factors. There is an urgent need to develop effective therapeutic drug. Natural medicines are rich resources for active lead compounds. They would provide new opportunities for the treatment of DN. The present study was designed to investigate the protective effects of Schisandrin B (SchB) on DN and to delineate the underlying mechanism. Oral administration of SchB in the diabetic mouse model significantly alleviated hyperglycemia-induced renal injury, which was accompanied by maintenance of urine creatinine and albumin levels at similar to those of control non-diabetic mice. Histological examination of renal tissue indicated that both development of fibrosis and renal cell apoptosis were dramatically inhibited by SchB. The protective effect of SchB on DN associated with suppression of inflammatory response and oxidative stress. These results strongly suggested that SchB could be a potential therapeutic agent for treatment of DN. Moreover, our findings provided a fuller understanding of the regulatory role of NF-κB and Nrf2 in DN, indicating that they could be important therapeutic targets.
Ursolic acid improves diabetic nephropathy via suppression of oxidative stress and inflammation in streptozotocin-induced rats.
Xu Hui-Lin,Wang Xu-Tao,Cheng Yin,Zhao Jin-Guo,Zhou Yu-Jie,Yang Jun-Jie,Qi Min-You
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
Inflammation plays a pivotal role in the pathogenesis of diabetic nephropathy (DN). Overexpression of inflammatory chemokine and cytokines is involved in the development of DN. Ursolic acid (UA), a common pentacyclic triterpenoid compound, has been reported to have myriad benefits and medicinal properties. However, its protective effects against renal injury in streptozotocin (STZ)-induced diabetic rats have not been firmly established. In the current report, we investigated whether UA inhibits oxidative stress and inflammation in the kidneys of STZ-induced diabetic rats. Diabetes mellitus (DM) was induced by STZ (40 mg/ kg, i.v.). Animals were randomly divided into control group (normal saline, i.g.), DN group (normal saline, i.g.), DN + UA group (35 mg/kg UA + normal saline, i.g.) and DN + telmisartan group (12 mg/kg telmisartan + normal saline, i.g.). Fasting blood glucose (FBG) levels were monitored at regular intervals. The administration of compounds started at 5 week and lasted for 8 weeks. At the beginning of 13 week, rats were humanely euthanized, KW/BW, BUN, SCr, SOD and MDA were measured. Histopathological changes in renal tissue were observed after hematoxylin-eosin (HE) staining. Furthermore, the expressions of TNF-α, MCP-1 and IL-1β in kidney were determined by immunohistochemistry and western blot. Our results showed that UA significantly lowered the levels of FBG, KW/BW, BUN, SCr and MDA in diabetic rats. Additionally, the SOD activity in UA treated group was higher than that in DN group. Furthermore, renal structural abnormalities and the elevation of TNF-α, MCP-1 and IL-1β expression level were blocked by the administration of UA. In conclusion, our data demonstrate that UA could be well used as a protective agent to counter renal dysfunction - through antioxidant and anti-inflammatory effects.
Activity of Group 2 Innate Lymphoid Cells is Associated with Chronic Inflammation and Dysregulated Metabolic Homoeostasis in Type 2 Diabetic Nephropathy.
Lu P,Ji X,Wan J,Xu H
Scandinavian journal of immunology
The metabolic syndrome (MS) is an independent risk factor for type 2 diabetic nephropathy and accompanied by subclinical inflammation which involves immune-deriving factors. Emerging studies indicate that group 2 innate lymphoid cells (ILC2s) can regulate adipose metabolism, but much less is known about the activity of ILC2s in metabolic imbalance in obesity and diabetes. This study explored the effect of ILC2s-related molecules on the occurrence of MS in type 2 diabetic nephropathy. Thirty patients with type 2 diabetic nephropathy were included in the study; the mRNA expression of ILC2s-associated molecules from peripheral blood mononuclear cell and the correlation of the ILC2s activity and the MS-related indicators were analysed. The results indicated that the waist circumference, fasting blood glucose, systolic blood pressure, diastolic blood pressure and triglyceride in patients with simple diabetes and diabetic nephropathy were increased, and the incidence of MS was 46.67% and 86.67%, respectively. The ILC2s-associated factors RORα, T1/ST2 and IL-5/IL-13 mRNA were increased in diabetic nephropathy. There was a positive correlation between the expression level of IL-13 or T1/ST2 mRNA and some MS indexes. In addition, the levels of plasma sTNFR, eotaxin-2 and I-309 were also increased in patients with type 2 diabetic nephropathy. It suggested that the patients with type 2 diabetic nephropathy were more likely to have multiple components of MS than those with simple type 2 diabetes mellitus, and enhanced ILC2s activity might be involved in the formation of MS in diabetic nephropathy via influencing blood pressure and lipid metabolism.
Lycium chinense leaves extract ameliorates diabetic nephropathy by suppressing hyperglycemia mediated renal oxidative stress and inflammation.
Olatunji Opeyemi Joshua,Chen Hongxia,Zhou Yifeng
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
Diabetic nephropathy is one of the most serious and most frequently encountered diabetic complication, accounting for the highest cause of end-stage renal disease. This present study was aimed at exploring the protective/attenuative effect of Lycium chinense leaf extract (MELC) on streptozotocin induced diabetic nephropathy in experimental Sprague Dawley rats. The oral administration of diabetic rats with MELC markedly ameliorated renal dysfunction as observed in the signiﬁcant reduction in the serum levels of creatinine, blood urea nitrogen (BUN), albumin and TGF-β1 as compared to the untreated diabetic control rats. In addition, the elevated levels of renal oxidative stress markers and pro-inflammatory parameters (GSH, SOD, CAT, MDA, TNF-α, IL-6 and IL-1β) were significantly reduced in MELC treated diabetic rats. The results obtained in this study suggests that L. chinense leaf might have the potential as possible pharmacological agent against diabetic nephropathy by suppressing renal oxidative stress and inﬂammation.
Globo-series glycosphingolipids enhance Toll-like receptor 4-mediated inflammation and play a pathophysiological role in diabetic nephropathy.
Nitta Takahiro,Kanoh Hirotaka,Inamori Kei-Ichiro,Suzuki Akemi,Takahashi Tomoko,Inokuchi Jin-Ichi
Alteration of glycosphingolipid (GSL) expression plays key roles in the pathogenesis and pathophysiology of many important human diseases, including cancer, diabetes and glycosphingolipidosis. Inflammatory processes are involved in development and progression of diabetic nephropathy, a major complication of type 2 diabetes mellitus. GSLs are known to play roles in inflammatory responses in various diseases, and levels of renal GSLs are elevated in mouse models of diabetic nephropathy; however, little is known regarding the pathophysiological role of these GSLs in this disease process. We studied proinflammatory activity of GSLs in diabetic nephropathy using spontaneously diabetic mouse strain KK. Mice were fed a high-fat diet (HFD) (60% kcal from fat) or normal diet (ND) (4.6% kcal from fat) for a period of 8 wk. HFD-feeding resulted in quantitative and qualitative changes of renal globo-series GSLs (particularly Gb3Cer), upregulation of TNF-α, and induction of renal inflammation. Gb3Cer/Gb4Cer treatment enhanced inflammatory responses via TLR4 in TLR4/MD-2 complex expressing cells, including HEK293T, mouse bone marrow-derived macrophages (BMDMs) and human monocytes. Our findings suggest that HFD-induced increase of Gb3Cer/Gb4Cer positively modulate TLR4-mediated inflammatory response, and that such GSLs play an important pathophysiological role in diabetic nephropathy.
Zinc supplementation alleviates the progression of diabetic nephropathy by inhibiting the overexpression of oxidative-stress-mediated molecular markers in streptozotocin-induced experimental rats.
Barman Susmita,Pradeep Seetur R,Srinivasan Krishnapura
The Journal of nutritional biochemistry
Zinc deficiency during diabetes projects a role for zinc nutrition in the management of diabetic nephropathy. The current study explored whether zinc supplementation protects against diabetic nephropathy through modulation of kidney oxidative stress and stress-induced expression related to the inflammatory process in streptozotocin-induced diabetic rats. Groups of hyperglycemic rats were exposed to dietary interventions for 6 weeks with zinc supplementation (5 times and 10 times the normal level). Supplemental-zinc-fed diabetic groups showed a significant reversal of increased kidney weight and creatinine clearance. There was a significant reduction in hyperlipidemic condition along with improved PUFA:SFA ratio in the renal tissue. Expression of the lipid oxidative marker and expression of inflammatory markers, cytokines, fibrosis factors and apoptotic regulatory proteins observed in diabetic kidney were beneficially modulated by zinc supplementation, the ameliorative effect being concomitant with elevated antiapoptosis. There was a significant reduction in advanced glycation, expression of the receptor of the glycated products and oxidative stress markers. Zinc supplementation countered the higher activity and expression of polyol pathway enzymes in the kidney. Overexpression of the glucose transporters, as an adaptation to the increased need for glucose transport in diabetic condition, was minimized by zinc treatment. The pathological abnormalities in the renal architecture of diabetic animals were corrected by zinc intervention. Thus, dietary zinc supplementation has a significant beneficial effect in the control of diabetic nephropathy. This was exerted through a protective influence on oxidative-stress-induced cytokines, inflammatory proliferation and consequent renal injury.
Modulating the gut microbiota and inflammation is involved in the effect of Bupleurum polysaccharides against diabetic nephropathy in mice.
Feng Yuchen,Weng Hongbo,Ling Lijun,Zeng Tao,Zhang Yunyi,Chen Daofeng,Li Hong
International journal of biological macromolecules
Dysbiosis of gut microbiota and low grade inflammation has gradually become a highly potential therapeutic agent for diabetic nephropathy (DN). It has been reported that a large number of polysaccharides have positive effects on DN, including Bupleurum polysaccharides. However, the mechanism remained unclear. This study selected two Bupleurum polysaccharides from different origins to investigate the potential relationship between kidney and gut. Diabetic mice model was established by streptozotocin (STZ, 100 mg/kg) and the treatment groups were treated with two Bupleurum polysaccharides (60 mg/kg) for 6 weeks, respectively. The results showed that the administration of Bupleurum polysaccharides ameliorated diabetic nephropathy induced by STZ. Blood glucose, blood creatinine and urine albumin were decreased after the oral administration of Bupleurum polysaccharides. And the dysbiosis of gut microbiota was modulated with higher diversity and gut protective microbiota. The gut barrier was also improved and the expression of inflammatory response both in kidney and colon was reduced. These results provided the evidence that modulating the gut microbiota and inflammation was involved in the effect of Bupleurum polysaccharides against diabetic nephropathy in mice and laid the foundation for the deeper, specific mechanism research on the interaction between kidney and gut.
ADMA reduction does not protect mice with streptozotocin-induced diabetes mellitus from development of diabetic nephropathy.
Rodionov Roman N,Heinrich Annett,Brilloff Silke,Jarzebska Natalia,Martens-Lobenhoffer Jens,Bode-Böger Stefanie M,Todorov Vladimir T,Hugo Christian P M,Weiss Norbert,Hohenstein Bernd
BACKGROUND AND AIMS:Cardiovascular disease is the major cause of morbidity and mortality in the world. Diabetes and its complications, such as diabetic nephropathy, dramatically increase cardiovascular risk. Association studies suggest that asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthases, plays a role in the pathogenesis of diabetic nephropathy. The major pathway of ADMA catabolism is hydrolysis by dimethylarginine dimethylaminohydrolase 1 (DDAH1). The goal of this study was to test the hypothesis that lowering ADMA by overexpression of DDAH1 protects from development of diabetic nephropathy. METHODS:Diabetes was induced with streptozotocin (STZ) in wild type and DDAH1 transgenic mice. Healthy mice served as controls. Mice were sacrificed after 20 weeks of diabetes. ADMA levels were assessed by isotope-dilution tandem mass spectrometry, creatinine by standard laboratory methods and albumin by ELISA. Kidney tissues were stained for markers of glomerular cells, cell matrix, inflammation and cell proliferation. RESULTS:STZ led to development of diabetes in all injected mice. Transgenic overexpression of DDAH1 led to a decrease in plasma ADMA levels in healthy animals. Diabetic state itself did not lead to elevation of plasma ADMA levels. Diabetic mice of both genotypes developed albuminuria (27 and 25 vs. 9 and 6 μg albumin/mg creatinine) (p < 0.01). There were no changes in glomerular matrix expansion, podocyte injury, inflammatory or proliferative response. CONCLUSIONS:STZ-induced diabetes led to the development of early features of diabetic nephropathy. Overexpression of DDAH1 and lowering of systemic ADMA levels did not prevent these changes, indicating that ADMA is not the major mediator of the early diabetic changes reflected by this experimental model.
Maximum home blood pressure is a useful indicator of diabetic nephropathy in patients with type 2 diabetes mellitus: KAMOGAWA-HBP study.
Oyabu Chikako,Ushigome Emi,Matsumoto Shinobu,Tanaka Toru,Hasegawa Goji,Nakamura Naoto,Ohnishi Masayoshi,Tsunoda Sei,Ushigome Hidetaka,Yokota Isao,Tanaka Muhei,Asano Mai,Yamazaki Masahiro,Fukui Michiaki
Diabetes & vascular disease research
OBJECTIVE:Maximum home systolic blood pressure has been shown to predict target organ damage. We aimed to clarify the association between maximum home systolic blood pressure and urine albumin to creatinine ratio, an indicator of early-phase diabetic nephropathy in patients with type 2 diabetes. METHODS:In 1040 patients, we assessed the relationship of mean or maximum home systolic blood pressure and urine albumin to creatinine ratio, and compared the area under the receiver operating characteristic curve of mean or maximum home systolic blood pressure for diabetic nephropathy (urine albumin to creatinine ratio ⩾30 mg/g Cr). RESULTS:Multivariate linear regression analyses indicated that mean morning systolic blood pressure ( β = 0.010, p < 0.001) and maximum morning systolic blood pressure ( β = 0.008, p < 0.001) were significantly associated with urine albumin to creatinine ratio. Area under the receiver operating characteristic curve (95% confidence interval) for diabetic nephropathy in mean and maximum morning systolic blood pressure was 0.667 (0.634-0.700; p < 0.001) and 0.671 (0.638-0.703; p < 0.001), respectively. CONCLUSION:Maximum home systolic blood pressure, as well as mean home systolic blood pressure, was significantly associated with diabetic nephropathy in patients with type 2 diabetes.
Low-Energy Extracorporeal Shock Wave Therapy Ameliorates Kidney Function in Diabetic Nephropathy.
Hsiao Chang-Chun,Huang Wei-Han,Cheng Kuang-Hung,Lee Chien-Te
Oxidative medicine and cellular longevity
Background:Diabetic nephropathy is the most common cause of end-stage renal disease. Traditional therapy for diabetic nephropathy has focused on supportive treatment, and there is no significant effective therapy. We investigated the effect of low-energy extracorporeal shock wave therapy on a diabetic nephropathy rat model. Methods:Streptozotocin-induced diabetic nephropathy rats were treated with six sessions of low-energy extracorporeal shock wave therapy (weekly for six consecutive weeks) or left untreated. We assessed urinary creatinine and albumin, glomerular volume, renal fibrosis, podocyte number, renal inflammation, oxidative stress, and tissue repair markers (SDF-1 and VEGF) six weeks after the completion of treatment. Results:The six-week low-energy extracorporeal shock wave therapy regimen decreased urinary albumin excretion as well as reduced glomerular hypertrophy and renal fibrosis in the rat model of diabetic nephropathy. Moreover, low-energy extracorporeal shock wave therapy increased podocyte number in diabetic nephropathy rats. This was likely primarily attributed to the fact that low-energy extracorporeal shock wave therapy reduced renal inflammation and oxidative stress as well as increased tissue repair potency and cell proliferation. Conclusions:Low-energy extracorporeal shock wave therapy preserved kidney function in diabetic nephropathy. Low-energy extracorporeal shock wave therapy may serve as a novel noninvasive and effective treatment of diabetic nephropathy.
The single-cell transcriptomic landscape of early human diabetic nephropathy.
Wilson Parker C,Wu Haojia,Kirita Yuhei,Uchimura Kohei,Ledru Nicolas,Rennke Helmut G,Welling Paul A,Waikar Sushrut S,Humphreys Benjamin D
Proceedings of the National Academy of Sciences of the United States of America
Diabetic nephropathy is characterized by damage to both the glomerulus and tubulointerstitium, but relatively little is known about accompanying cell-specific changes in gene expression. We performed unbiased single-nucleus RNA sequencing (snRNA-seq) on cryopreserved human diabetic kidney samples to generate 23,980 single-nucleus transcriptomes from 3 control and 3 early diabetic nephropathy samples. All major cell types of the kidney were represented in the final dataset. Side-by-side comparison demonstrated cell-type-specific changes in gene expression that are important for ion transport, angiogenesis, and immune cell activation. In particular, we show that the diabetic thick ascending limb, late distal convoluted tubule, and principal cells all adopt a gene expression signature consistent with increased potassium secretion, including alterations in Na/K-ATPase, , mineralocorticoid receptor, and expression, as well as decreased paracellular calcium and magnesium reabsorption. We also identify strong angiogenic signatures in glomerular cell types, proximal convoluted tubule, distal convoluted tubule, and principal cells. Taken together, these results suggest that increased potassium secretion and angiogenic signaling represent early kidney responses in human diabetic nephropathy.
Diabetic Nephropathy Following Posttransplant Diabetes Mellitus.
Nagib Ayman Maher,Elsayed Matter Yasser,Gheith Osama Ashry,Refaie Ayman Fathi,Othman Nashwa Farouk,Al-Otaibi Torki
Experimental and clinical transplantation : official journal of the Middle East Society for Organ Transplantation
Diabetic nephropathy is one of the main long-term diabetic microangiopathies that can complicate type 1 and 2 and other secondary forms of diabetes mellitus, including posttransplant diabetes mellitus. Posttransplant diabetes mellitus was initially reported in the 1960s, with case reports of recurrent and de novo diabetic nephropathy after kidney transplant reported in the early 2000s, mostly as a result of same-risk and precipitating factors of diabetic nephropathy as in native kidneys. The disease may appear early in view of the hyperfiltration risk of being a single grafted kidney. Here, we discuss risk factors, early serologic and genetic biomarkers for early detection, and strategies to avoid and delay the progression of diabetic nephropathy after posttransplant diabetes mellitus. In this overview of published literatures, we searched PubMed and MEDLINE for all articles published in English language between January 1994 and July 2018. Included studies reported on the prevalence, incidence, or determinants of post-transplant diabetes among renal transplant recipients and studies reporting diabetic nephropathy in their cohorts. Our review showed that avoidance or good control of posttransplant diabetes is the cornerstone in management of posttransplant diabetes mellitus and hence diabetic nephropathy. Control and avoidance can be commenced in the preparatory stage before transplant using validated genetic markers that can predict posttransplant diabetes mellitus. The use of well-matched donors with tailored immunosuppression (using less diabetogenic agents and possibly steroid-free regimens) and lifestyle modifications are the best preventative strategies. Tight glycemic control, early introduction of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, and possibly conversion to less diabetogenic regimens can help to delay progression of diabetic nephropathy.
Elevated Levels of Protein Carbonylation in Patients With Diabetic Nephropathy: Therapeutic and Diagnostic Prospects.
Almogbel Ebtehal,Rasheed Naila
The American journal of the medical sciences
BACKGROUND:Oxidative stress-induced protein oxidation has been reported in diabetes mellitus; however a relationship between protein carbonylation and diabetic nephropathy remains to be determined. This study was undertaken to investigate a correlation between protein carbonylation and diabetic nephropathy. METHODS:Sera from 153 patients with diabetic nephropathy and 142 healthy humans were selected and protein carbonylation was compared. The glycated hemoglobin (Hb), postprandial blood glucose (PPBG), disease duration (DD) and serum creatinine were analyzed and were correlated with the levels of protein oxidation. RESULTS:Protein carbonylation was more pronounced in patients with diabetic nephropathy as compared with healthy humans (P < 0.001). The data showed a positive correlation between protein oxidation and Hb (P < 0.001, r = 0.752); the carbonylation was high in those patients with high Hb (P < 0.01). The data also showed an important correlation between protein oxidation and PPBG (P < 0.0001, r = 0.680); the carbonyl contents were higher in those patients with higher PPBG (P < 0.001). Results also pointed out a positive correlation of protein oxidation with patients DD (P < 0.001, r = 0.769). Importantly, elevated levels of carbonylation in patients with diabetic nephropathy were also correlated with the elevated levels of serum creatinine. CONCLUSIONS:This is the first study that shows a positive correlation between protein carbonylation and diabetic nephropathy. The higher carbonylation in patients with higher Hb blood glucose, DD or serum creatinine indicate that oxidative modifications in proteins play a key role in the progression of diabetic nephropathy.
The Signaling of Cellular Senescence in Diabetic Nephropathy.
Xiong Yabing,Zhou Lili
Oxidative medicine and cellular longevity
Diabetic nephropathy is the leading cause of chronic kidney disease (CKD) in western countries. Notably, it has a rapidly rising prevalence in China. The patients, commonly complicated with cardiovascular diseases and neurologic disorders, are at high risk to progress into end-stage renal disease (ESRD) and death. However, the pathogenic mechanisms of diabetic nephropathy have not been determined. Cellular senescence, which recently has gained broad attention, is thought to be an important player in the onset and development of diabetic nephropathy. In this issue, we generally review the mechanisms of cellular senescence in diabetic nephropathy, which involve telomere attrition, DNA damage, epigenetic alterations, mitochondrial dysfunction, loss of Klotho, Wnt/-catenin signaling activation, persistent inflammation, and accumulation of uremic toxins. Moreover, we highlight the potential therapeutic targets of cellular senescence in diabetic nephropathy and provide important clues for clinical strategies.
Wnt signaling and podocyte dysfunction in diabetic nephropathy.
Bose Madhura,Almas Sadia,Prabhakar Sharma
Journal of investigative medicine : the official publication of the American Federation for Clinical Research
Nephropathy is a major microvascular complication of diabetes mellitus and often leads to terminal renal failure in addition to contributing significantly to cardiovascular morbidity and mortality. Despites continuous advances, the pathogenesis of diabetic nephropathy remains poorly understood. Recent studies have underscored the significance of structural and functional changes in podocytes in the development and progression of diabetic nephropathy. The role of podocytes in health and diabetic nephropathy and abnormalities including podocyte hypertrophy, effacement, and apoptosis, and a detailed discussion on the role played by the Wnt-β-catenin signaling pathway in podocyte injury and dysfunction are the focus of this review. In addition, the role played by Wnt signaling in mediating the effects of known therapeutic strategies for diabetic nephropathy is also discussed.
Role of Vitamin D and Its Analogues in Diabetic Nephropathy: A Meta-analysis.
Gupta Sonali,Goyal Pradeep,Feinn Richard S,Mattana Joseph
The American journal of the medical sciences
BACKGROUND:Diabetic nephropathy remains one of the most common causes of chronic kidney disease in the United States and is associated with significant morbidity and mortality. Recently, there have been emerging data highlighting the role of vitamin D and its analogue in chronic kidney disease especially diabetic nephropathy independent of its effect on bone metabolism. METHODS:This study aimed to evaluate effect of supplementing vitamin D and its analogues on halting or slowing progression of diabetic nephropathy. Electronic databases (PubMed, Scopus, Google scholar) were searched and randomized controlled trials (RCTs) that investigated the use of vitamin D and its analogs for diabetic nephropathy were studied. This meta-analysis of RCTs performed in accordance with Preferred Reporting Items for Systematic review and Meta-analysis statement. RESULTS:This meta-analysis included 9 RCTs and suggested a favorable trend with respect to an effect of vitamin D and its analogues on albuminuria though this did not reach statistical significance (MD, -0.17; 95% CI, -0.34-0.01; P = 0.06]. Serum calcium was unaffected suggesting safe use of these agents. CONCLUSIONS:Use of vitamin D and its analogues may have potential as an adjuvant therapy for reducing albuminuria and slowing progression of diabetic nephropathy but further studies are needed.
Common Drugs for Stabilization of Renal Function in the Progression of Diabetic Nephropathy and Their Relations with Hypertension Therapy.
Wang Yuxuan,Wang Chengcheng,Zhang Xiuli,Gu Harvest F,Wu Liang
Current diabetes reviews
INTRODUCTION:Diabetic nephropathy is characterized by hypertension, progressive albuminuria, glomerulosclerosis and declines in glomerular filtration rate leading to end stage renal disease. Although the pathogenesis of diabetic nephropathy is not fully understood, current treatment of the patients with diabetic nephropathy is mainly based upon the control of hyperglycaemia and management of blood pressures. BACKGROUND:Several drugs, which are originally developed for hypertension therapy, have been adopted for stabilization of renal function in diabetic nephropathy. In this review, we first discussed the relationships between diabetic nephropathy and hypertension particularly in the renin-angiotensinaldosterone system. We then summarized chemical structures, pharmacological characteristics and clinical studies of the common drugs used for treatment of diabetic nephropathy, while these drugs have effects against hypertension. CONCLUSION:This review may provide the constructive information for further drug development in diabetic nephropathy.
Effect of AMP-activated protein kinase subunit alpha 2 (PRKAA2) genetic polymorphisms on susceptibility to type 2 diabetes mellitus and diabetic nephropathy in a Chinese population.
Li Qingchu,Li Cuilin,Li Haoyun,Zeng Liu,Kang Zhiqiang,Mao Yu,Tang Xinyue,Zheng Panpan,He Li,Luo Fang,Li Zhi
Journal of diabetes
BACKGROUND:It is well known that AMP-activated protein kinase (AMPK) is a key factor affecting the development of type 2 diabetes mellitus (T2DM). The single nucleotide polymorphism (SNP) rs2746342 in the AMPK alpha 2 subunit gene (PRKAA2) has been found to be associated with susceptibility to T2DM in the Chinese Han population. The present study further investigates the association of PRKAA2 genotypes with susceptibility to T2DM and its complication, diabetic nephropathy. METHODS:The PRKAA2 genotypes of 406 T2DM patients and 214 controls from the Chinese Han population were determined with regard to SNPs rs10789038, rs2796498 and rs2746342. The association between these SNPs and susceptibility to T2DM and diabetic nephropathy was evaluated. The clinical characteristics differed significantly between T2DM patients and controls. RESULTS:After adjustment for age, sex and body mass index, there was an obvious relationship between T2DM and both rs10789038 (odds ratio [OR] 1.634; P = 0.015) and rs2796498 (OR 0.656; P = 0.030), but not rs2746342. There was haplotype association of PRKAA2 rs10789038-rs2796498-rs2746342 with T2DM susceptibility. In addition, rs2796498 was found to be related to the susceptibility to diabetic nephropathy. CONCLUSIONS:Polymorphisms in rs10789038 and rs2796498 are associated with the susceptibility to T2DM, and rs2796498 may be related to diabetic nephropathy.
Salidroside stimulates the Sirt1/PGC-1α axis and ameliorates diabetic nephropathy in mice.
Xue Haiyan,Li Peipei,Luo Yishu,Wu Chuwen,Liu Yue,Qin Xiaogang,Huang Xinzhong,Sun Cheng
Phytomedicine : international journal of phytotherapy and phytopharmacology
BACKGROUND:Salidroside, an active component from Traditional Chinese Medicine Rhodiola rosea L., has various pharmacological functions including anti-inflammatory, anti-cancer and anti-oxidative properties. However, whether salidroside plays a beneficial role in diabetic nephropathy is still unclear. PURPOSE:The objective of this work was to investigate the potential roles of salidroside against diabetic nephropathy and the underlying molecular mechanisms. METHODS:Streptozocin was given to obese mice to generate diabetic nephropathy animal model. Salidroside was administered to these mice and proteinuria, podocyte integrity, renal morphology and fibrosis, mitochondrial biogenesis were examined. RESULTS:Our results showed that salidroside treatment greatly attenuates diabetic nephropathy as evidenced by decreased urinary albumin, blood urea nitrogen and serum creatinine. Morphological analysis indicated that salidroside improves renal structures in diabetic nephropathy. The decreases in nephrin and podocin expression were markedly reversed by salidroside. Moreover, kidney fibrosis in diabetic nephropathy mice was largely prevented by salidroside. Mechanistically, in salidroside-treated mice, the mitochondrial DNA copy and electron transport chain proteins were significantly enhanced. Meanwhile, the reduced Sirt1 and PGC-1α expression in diabetic nephropathy was almost completely counteracted in the presence of salidroside. CONCLUSIONS:Our data showed that salidroside plays a beneficial role against diabetic nephropathy in mice, which probably via Sirt1/PGC-1α mediated mitochondrial biogenesis.
Update on Diabetic Nephropathy: Core Curriculum 2018.
Umanath Kausik,Lewis Julia B
American journal of kidney diseases : the official journal of the National Kidney Foundation
Diabetic kidney disease and diabetic nephropathy are the leading cause of end-stage kidney disease in the United States and most developed countries. Diabetes accounts for 30% to 50% of the incident cases of end-stage kidney disease in the United States. Although this represents a significant public health concern, it is important to note that only 30% to 40% of patients with diabetes develop diabetic nephropathy. Specific treatment of patients with diabetic nephropathy can be divided into 4 major arenas: cardiovascular risk reduction, glycemic control, blood pressure control, and inhibition of the renin-angiotensin system (RAS). Recommendations for therapy include targeting a hemoglobin A concentration < 7% and blood pressure < 140/90mmHg with therapy anchored around the use of a RAS-blocking agent. The single best evidence-based therapy for diabetic nephropathy is therapy with a RAS-blocking medication. This Core Curriculum outlines and discusses in detail the epidemiology, pathophysiology, diagnosis, and management of diabetic nephropathy.
Glomerular mesangial cell and podocyte injuries in diabetic nephropathy.
Tung Chun-Wu,Hsu Yung-Chien,Shih Ya-Hsueh,Chang Pey-Jium,Lin Chun-Liang
Nephrology (Carlton, Vic.)
Diabetic nephropathy is one of the leading causes of end-stage renal disease and creates heavy healthcare burdens globally. Dysfunction of mesangial cells and podocytes contributes to diabetic nephropathy. Dysregulation of signaling involved in renal development and regeneration may cause diabetic kidney damages. Growing evidences suggest the importance of dysregulated dickkopf-1 (DKK1)/Wnt/ β-catenin signaling pathways in the pathogenesis of diabetic glomerular injuries. The inhibition of Wnt signaling in injured mesangial cells is likely attributed to the high glucose-induced Ras/Rac1 dependent superoxide formation. When DKK1, the cellular inhibitor of Wnt signaling, binds to the Kremen-2 receptor, depositions of extracellular matrix increase in the mesangium of diabetic kidneys. Additionally, reactivation of Notch-1 signaling has been implicated in podocytopathy during diabetic proteinuria development. Knocking down Notch-1 alleviates vascular endothelial growth factor (VEGF) expression, nephrin repression and proteinuria in diabetic kidneys. It is also found that epigenetic modulations by histone deacetylase 4 (HDAC4) and miR-29a could lead to diabetic nephropathy. High glucose increases the expression of HDAC4, which causes deacetylation with subsequent ubiquitination of nephrin. Overexpression of miR-29a in diabetic transgenic mice would decrease the expression of HDAC4 and stabilize nephrin. Surprisingly, reprogramming or reactivation of signaling involved in renal development or regeneration often brings about diabetic glomerular sclerosis in mesangial cells and podocytes. Better knowledge about modifications of embryonic stem cell signaling will have a chance to implement strategically focused pharmacological research programs aiming to the development of new drugs for diabetic kidney injuries.
Impact of EGCG Supplementation on the Progression of Diabetic Nephropathy in Rats: An Insight into Fibrosis and Apoptosis.
Mohan Thangarajeswari,Velusamy Prema,Chakrapani Lakshmi Narasimhan,Srinivasan Ashok Kumar,Singh Abhilasha,Johnson Thanka,Periandavan Kalaiselvi
Journal of agricultural and food chemistry
Apoptosis is an active response of cells to altered microenvironments, which is characterized by cell shrinkage, chromatin condensation, and DNA fragmentation, in a variety of cell types such as renal epithelial cells, endothelial cells, mesangial cells, and podocytes. Hyperglycemia is among the microenvironmental factors that may facilitate apoptosis, which plays a decisive role in the initiation of diabetic nephropathy. Transforming growth factor-β emerges as a powerful fibrogenic factor in the development of renal hypertrophy. Although, a number of potential treatment strategies exist for diabetic nephropathy, considering the ease of use and bioavailability, phytochemicals stands distinct as the preeminent option. EGCG, a green tea catechin is one such phytochemical which possesses hypoglycemic and antifibrotic activity. The present study aims to explore the potential of EGCG to prevent apoptosis in a high-fat diet and STZ induced diabetic nephropathy rats by assessing renal function, pro-fibrotic marker, and the expression of apoptotic and antiapoptotic proteins. Our results validate EGCG as a potential antiapoptotic agent evidently by improving renal function via down regulating TGF-β, consequently ameliorating diabetic nephropathy. In accordance with this, EGCG might be regarded as a prospective therapeutic candidate in modulating diabetic nephropathy, thus being a promising treatment.
Sarcopenia in diabetic nephropathy: a cross-sectional study.
Çeliker Meral,Selçuk Mustafa Yavuz,Olt Serdar
Romanian journal of internal medicine = Revue roumaine de medecine interne
OBJECTIVE:To investigate the relationship between sarcopenia and diabetic nephropathy. METHODS:56 diabetic patients without complications, 50 diabetic patients with nephropathy, 53 healthy controls included in this present study. Demographic characteristics such as sex, age, anthropometric measurements such as weight, body mass index [BMI], hip circumference, waist circumference and upper arm circumference were measured. Sarcopenia diagnosis was based on European Working Group on Sarcopenia in Older People [EWGSOP] criteria which consist of hand grip strength, 6-meter walking test and muscle mass. RESULTS:The frequency of sarcopenia increased gradually from 15.1% in healthy control group to 21.4% in the diabetes group, and 34% in diabetic nephropathy group (X2 for trend, p = 0.029). The frequency of sarcopenia was similar in diabetes and diabetic nephropathy group. However, the frequency of sarcopenia was higher in diabetic nephropathy than healthy controls (OR = 2.89, CI [1.11-7.51] in logistic regression). CONCLUSION:In the present study, the prevalence of sarcopenia was higher in patients with diabetic nephropathy compared to healthy controls.
The effects of vitamin D supplementation on some metabolic and inflammatory markers in diabetic nephropathy patients with marginal status of vitamin D: A randomized double blind placebo controlled clinical trial.
Esfandiari A,Pourghassem Gargari B,Noshad H,Sarbakhsh P,Mobasseri M,Barzegari M,Arzhang P
Diabetes & metabolic syndrome
AIMS:Diabetic nephropathy is known to be an independent risk factor in the progression of renal and cardiovascular disorders. Due to the association between vitamin D deficiency and diabetic nephropathy, vitamin D deficiency in the diabetic nephropathy population, this study conducted to examine the effects of Vitamin D on metabolic and inflammatory parameters in patients with diabetic nephropathy. METHODS:This eight-week, randomized, double-blind, placebo-controlled trial was carried out on 50 diabetic nephropathy patients with marginal status of vitamin D. Participants were randomly assigned to two groups: control and intervention. Participants received a vitamin D3 (50000 IU) supplement weekly on a specific day. Fasting blood samples were collected from all patients at their entry to the study, and eight weeks after intervention. RESULTS:Analyses showed significance differences in physical activity between the intervention and placebo groups (P = 0.018). There were no significant differences between the percentage changes of HbA1c, insulin and, inflammatory parameters such as TNF-α and IL-6 (P > 0.05), while the percentage change of FBS was significantly higher in the placebo group compared to the treatment one (P < 0.0001). Lower levels of FBS (P < 0.0001), insulin (P < 0.069), HOMA-IR (P < 0.001), TNF-α (P< 0.002) and IL-6 (P < 0.037) were found after supplementation in treatment group. However, the phosphorous and protein percentage change in urine were lower (P = 0.07) and higher (P = 0.003) between groups. CONCLUSIONS:It was found that vitamin D supplementation can be regarded as an effective way to prevent the progression of diabetic nephropathy by reducing levels of proteinuria, and inflammatory markers such as TNF-α and IL-6.
Diabetic nephropathy is associated with frailty in patients with chronic hemodialysis.
Kakio Yuki,Uchida Haruhito A,Takeuchi Hidemi,Okuyama Yuka,Okuyama Michihiro,Umebayashi Ryoko,Wada Kentaro,Sugiyama Hitoshi,Sugimoto Ken,Rakugi Hiromi,Kasahara Shingo,Wada Jun
Geriatrics & gerontology international
AIM:Since 1998, the leading cause of chronic hemodialysis in Japan has been diabetic nephropathy. Diabetes mellitus is known to be a risk factor for frailty, but it still remains unknown whether diabetic nephropathy is associated with frailty in chronic dialysis patients. The authors carried out the present study to reveal the association between frailty and diabetic nephropathy in chronic hemodialysis patients. METHODS:A total of 355 patients who were on hemodialysis were recruited. Participants were divided into two groups of either patients who suffered diabetic nephropathy with end-stage renal disease (DN group, n = 150) or not (Non-DN group, n = 205). The authors investigated the difference of the prevalence of frailty between the two groups. Furthermore, the authors examined the risk factors for frailty. RESULTS:The prevalence of frailty in the DN group was significantly higher than that in the Non-DN group (28.0% vs 16.5%, P = 0.0161). To evaluate the association between frailty and its risk factors, we compared frail patients (n = 71) and non-frail patients (n = 262). After adjusting their interrelationships by using multivariate logistic regression analysis, diabetic nephropathy was determined as a significant risk factor for frailty. CONCLUSIONS:The authors found the close association between frailty and diabetic nephropathy in chronic hemodialysis patients. Geriatr Gerontol Int 2018; 18: 1597-1602.
Soluble receptor for AGE in diabetic nephropathy and its progression in Finnish individuals with type 1 diabetes.
Wadén Jenny M,Dahlström Emma H,Elonen Nina,Thorn Lena M,Wadén Johan,Sandholm Niina,Forsblom Carol,Groop Per-Henrik,
AIMS/HYPOTHESIS:Activation of the receptor for AGE (RAGE) has been shown to be associated with diabetic nephropathy. The soluble isoform of RAGE (sRAGE) is considered to function as a decoy receptor for RAGE ligands and thereby protects against diabetic complications. A possible association between sRAGE and diabetic nephropathy is still, however, controversial and a more comprehensive analysis of sRAGE with respect to diabetic nephropathy in type 1 diabetes is therefore warranted. METHODS:sRAGE was measured in baseline serum samples from 3647 participants with type 1 diabetes from the nationwide multicentre Finnish Diabetic Nephropathy (FinnDiane) Study. Associations between sRAGE and diabetic nephropathy, as well as sRAGE and diabetic nephropathy progression, were evaluated by regression, competing risks and receiver operating characteristic curve analyses. The non-synonymous SNP rs2070600 (G82S) was used to test causality in the Mendelian randomisation analysis. RESULTS:Baseline sRAGE concentrations were highest in participants with diabetic nephropathy, compared with participants with a normal AER or those with microalbuminuria. Baseline sRAGE was associated with progression from macroalbuminuria to end-stage renal disease (ESRD) in the competing risks analyses, but this association disappeared when eGFR was entered into the model. The SNP rs2070600 was strongly associated with sRAGE concentrations and with progression from macroalbuminuria to ESRD. However, Mendelian randomisation analysis did not support a causal role for sRAGE in progression to ESRD. CONCLUSIONS/INTERPRETATION:sRAGE is associated with progression from macroalbuminuria to ESRD, but does not add predictive value on top of conventional risk factors. Although sRAGE is a biomarker of diabetic nephropathy, in light of the Mendelian randomisation analysis it does not seem to be causally related to progression from macroalbuminuria to ESRD.
Fibroblast growth factor 1 ameliorates diabetic nephropathy by an anti-inflammatory mechanism.
Liang Guang,Song Lintao,Chen Zilu,Qian Yuanyuan,Xie Junjun,Zhao Longwei,Lin Qian,Zhu Guanghui,Tan Yi,Li Xiaokun,Mohammadi Moosa,Huang Zhifeng
Inflammation plays a central role in the etiology of diabetic nephropathy, a global health issue. We observed a significant reduction in the renal expression of fibroblast growth factor 1, a known mitogen and insulin sensitizer, in patients with diabetic nephropathy and in mouse models implying that fibroblast growth factor 1 possesses beneficial anti-inflammatory and renoprotective activities in vivo. To test this possibility, we investigated the effects of chronic intraperitoneal administration of fibroblast growth factor 1 into both the streptozotocin-induced type 1 diabetes and db/db type 2 diabetes models. Indeed, recombinant fibroblast growth factor 1 significantly suppressed renal inflammation (i.e., cytokines, macrophage infiltration), glomerular and tubular damage, and renal dysfunction in both type 1 and type 2 diabetes mice. Fibroblast growth factor 1 was able to correct the elevated blood glucose levels in type 2 but not in type 1 diabetic mice, suggesting that the anti-inflammatory effect of fibroblast growth factor 1 was independent of its glucose-lowering activity. The mechanistic study demonstrated that fibroblast growth factor 1-mediated inhibition of the renal inflammation in vivo was accompanied by attenuation of the nuclear factor κB and c-Jun N-terminal kinase signaling pathways, further validated in vitro using cultured glomerular mesangial cells and podocytes. Thus, fibroblast growth factor 1 holds great promise for developing new treatments for diabetic nephropathy through countering inflammatory signaling cascades in injured renal tissue.