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Co-expression analysis among microRNAs, long non-coding RNAs, and messenger RNAs to understand the pathogenesis and progression of diabetic kidney disease at the genetic level. Zhang Lihua,Li Rong,He Junyi,Yang Qiuping,Wu Yanan,Huang Jingshan,Wu Bin Methods (San Diego, Calif.) Diabetic kidney disease (DKD) is a serious disease that presents a major health problem worldwide. There is a desperate need to explore novel biomarkers to further facilitate the early diagnosis and effective treatment in DKD patients, thus preventing them from developing end-stage renal disease (ESRD). However, most regulation mechanisms at the genetic level in DKD still remain unclear. In this paper, we describe our innovative methodologies that integrate biological, computational, and statistical approaches to investigate important roles performed by regulations among microRNAs (miRs), long non-coding RNAs (lncRNAs), and messenger RNAs (mRNAs) in DKD. We conducted fully transparent, rigorously designed experiments. Our robust and reproducible results identified hsa-miR-223-3p as a candidate novel biomarker performing important roles in DKD disease process. 10.1016/j.ymeth.2017.05.023
Mitochondrial reactive oxygen species in the pathogenesis of early diabetic nephropathy. Nishikawa Takeshi,Brownlee Michael,Araki Eiichi Journal of diabetes investigation 10.1111/jdi.12258
Resveratrol protects diabetic kidney by attenuating hyperglycemia-mediated oxidative stress and renal inflammatory cytokines via Nrf2-Keap1 signaling. Palsamy P,Subramanian S Biochimica et biophysica acta Hyperglycemia-mediated oxidative stress plays a crucial role in the progression of diabetic nephropathy. Hence, the present study was hypothesized to explore the renoprotective nature of resveratrol by assessing markers of oxidative stress, proinflammatory cytokines and antioxidant competence in streptozotocin-nicotinamide-induced diabetic rats. Oral administration of resveratrol to diabetic rats showed a significant normalization on the levels of creatinine clearance, plasma adiponectin, C-peptide and renal superoxide anion, hydroxyl radical, nitric oxide, TNF-α, IL-1β, IL-6 and NF-κB p65 subunit and activities of renal aspartate transaminase, alanine transaminase and alkaline phosphatase in comparison with diabetic rats. The altered activities of renal aldose reductase, sorbitol dehydrogenase and glyoxalase-I and elevated level of serum advanced glycation end products in diabetic rats were also reverted back to near normalcy. Further, resveratrol treatment revealed a significant improvement in superoxide dismutase, catalase, glutathione peroxidase, glutathione-S-transferase and glutathione reductase activities and vitamins C and E, and reduced glutathione levels, with a significant decline in lipid peroxides, hydroperoxides and protein carbonyls levels in diabetic kidneys. Similarly, mRNA and protein analyses substantiated that resveratrol treatment notably normalizes the renal expression of Nrf2/Keap1and its downstream regulatory proteins in the diabetic group of rats. Histological and ultrastructural observations also evidenced that resveratrol effectively protects the kidneys from hyperglycemia-mediated oxidative damage. These findings demonstrated the renoprotective nature of resveratrol by attenuating markers of oxidative stress in renal tissues of diabetic rats. 10.1016/j.bbadis.2011.03.008
CXCL6 Promotes Renal Interstitial Fibrosis in Diabetic Nephropathy by Activating JAK/STAT3 Signaling Pathway. Sun Meng-Yao,Wang Su-Juan,Li Xiao-Qin,Shen Yu-Li,Lu Jian-Rao,Tian Xin-Hui,Rahman Khalid,Zhang Li-Jun,Nian Hua,Zhang Hong Frontiers in pharmacology In this study the role of CXCL6 in diabetic nephropathy (DN) was investigated. It was found to be overexpression in DN patients and DN rat model. And the expression of fibrosis-related cytokines was consistent with the expression of CXCL6. High glucose significantly increased the proliferation of rat renal fibroblasts NRK-49F cell and the expression of CXCL6. Knockdown of CXCL6 ameliorated the pro-proliferation effect of high glucose and decreased the expression of fibrosis-related cytokines, while CXCL6 overexpression exhibited the opposite phenomenon. Gene set enrichment analysis, Western blot and ELISA showed that Janus kinase-signal transducer and activator of transcription (JAK-STAT) and CYTOKINE_CYTOKINE_RECEPTOR_INTERACTION signaling pathways were correlative with CXCL6. This data indicates that CXCL6 may promote fibrosis-related factors to accelerate the development of DN renal interstitial fibrosis by activating JAK/STAT3 signaling pathway. CXCL6 is promising to be a potential novel therapeutic target and candidate biomarker for JAK/STAT3 signaling for the treatment of DN. 10.3389/fphar.2019.00224
Insulin Inhibits Nrf2 Gene Expression via Heterogeneous Nuclear Ribonucleoprotein F/K in Diabetic Mice. Ghosh Anindya,Abdo Shaaban,Zhao Shuiling,Wu Chin-Han,Shi Yixuan,Lo Chao-Sheng,Chenier Isabelle,Alquier Thierry,Filep Janos G,Ingelfinger Julie R,Zhang Shao-Ling,Chan John S D Endocrinology Oxidative stress induces endogenous antioxidants via nuclear factor erythroid 2-related factor 2 (Nrf2), potentially preventing tissue injury. We investigated whether insulin affects renal Nrf2 expression in type 1 diabetes (T1D) and studied its underlying mechanism. Insulin normalized hyperglycemia, hypertension, oxidative stress, and renal injury; inhibited renal Nrf2 and angiotensinogen (Agt) gene expression; and upregulated heterogeneous nuclear ribonucleoprotein F and K (hnRNP F and hnRNP K) expression in Akita mice with T1D. In immortalized rat renal proximal tubular cells, insulin suppressed Nrf2 and Agt but stimulated hnRNP F and hnRNP K gene transcription in high glucose via p44/42 mitogen-activated protein kinase signaling. Transfection with small interfering RNAs of p44/42 MAPK, hnRNP F, or hnRNP K blocked insulin inhibition of Nrf2 gene transcription. Insulin curbed Nrf2 promoter activity via a specific DNA-responsive element that binds hnRNP F/K, and hnRNP F/K overexpression curtailed Nrf2 promoter activity. In hyperinsulinemic-euglycemic mice, renal Nrf2 and Agt expression was downregulated, whereas hnRNP F/K expression was upregulated. Thus, the beneficial actions of insulin in diabetic nephropathy appear to be mediated, in part, by suppressing renal Nrf2 and Agt gene transcription and preventing Nrf2 stimulation of Agt expression via hnRNP F/K. These findings identify hnRNP F/K and Nrf2 as potential therapeutic targets in diabetes. 10.1210/en.2016-1576
Hemin therapy improves kidney function in male streptozotocin-induced diabetic rats: role of the heme oxygenase/atrial natriuretic peptide/adiponectin axis. Ndisang Joseph Fomusi,Jadhav Ashok Endocrinology Diabetic nephropathy is characterized by elevated macrophage infiltration and inflammation. Although heme-oxygenase (HO) is cytoprotective, its role in macrophage infiltration and nephropathy in type 1 diabetes is not completely elucidated. Administering the HO inducer, hemin, to streptozotocin-diabetic rats suppressed renal proinflammatory macrophage-M1 phenotype alongside several proinflammatory agents, chemokines, and cytokines including macrophage inflammatory protein 1α (MIP-1α), macrophage-chemoattractant protein-1 (MCP-1), TNF-α, IL-1β, IL-6, nuclear factor-κB (NF-κB), and aldosterone, a stimulator of the inflammatory/oxidative transcription factor, NF-κB. Similarly, hemin therapy attenuated extracellular matrix/profibrotic proteins implicated in renal injury including fibronectin, collagen-IV, and TGF-β1 and reduced several renal histopathological lesions such as glomerulosclerosis, tubular necrosis, tubular vacuolization, and interstitial macrophage infiltration. Furthermore, hemin reduced markers of kidney dysfunction like proteinuria and albuminuria but increased creatinine clearance, suggesting improved kidney function. Correspondingly, hemin significantly enhanced the antiinflammatory macrophage-M2 phenotype, IL-10, adiponectin, HO-1, HO activity, and atrial natriuretic-peptide (ANP), a substance that abates TNF-α, IL-6, and IL-1β, with parallel increase of urinary cGMP, a surrogate marker of ANP. Contrarily, coadministering the HO inhibitor, chromium-mesoporphyrin with the HO-inducer, hemin nullified the antidiabetic and renoprotective effects, whereas administering chromium-mesoporphyrin alone abrogated basal HO activity, reduced basal adiponectin and ANP levels, aggravated hyperglycemia, and further increased MCP-1, MIP-1α, aldosterone, NF-κB, TNF-α, IL-6, IL-1β, proteinuria/albuminuria, and aggravated creatinine clearance, thus exacerbating renal dysfunction, suggesting the importance of the basal HO-adiponectin-ANP axis in renoprotection and kidney function. Collectively, these data suggest that hemin ameliorates diabetic nephropathy by selectively enhancing the antiinflammatory macrophage-M2 phenotype and IL-10 while concomitantly abating the proinflammatory macrophage-M1 phenotype and suppressing extracellular matrix/profibrotic factors with reduction of renal lesions including interstitial macrophage infiltration. Because aldosterone stimulate NF-κB, which activates cytokines like TNF-α, IL-6, IL-1β that in turn stimulate chemokines such as MCP-1 and MIP-1α to promote macrophage-M1 infiltration, the hemin-dependent potentiation of the HO-adiponectin-ANP axis may account for reduced macrophage infiltration and inflammatory insults in streptozotocin-diabetic rats. 10.1210/en.2013-1050
FoxO1 Promotes Mitophagy in the Podocytes of Diabetic Male Mice via the PINK1/Parkin Pathway. Li Wen,Du Mengmeng,Wang Qingzhu,Ma Xiaojun,Wu Lina,Guo Feng,Ji Hongfei,Huang Fengjuan,Qin Guijun Endocrinology We recently showed that forkhead-box class O1 (FoxO1) activation protects against high glucose-induced injury by preventing mitochondrial dysfunction in the rat kidney cortex. In addition, FoxO1 has been reported to mediate putative kinase 1 (PINK1) transcription and promote autophagy in response to mitochondrial oxidative stress in murine cardiomyocytes. In this study, we ascertained whether overexpressing FoxO1 in the kidney cortex reverses preestablished diabetic nephropathy in animal models. The effect of FoxO1 on mitophagy signaling pathways was evaluated in mouse podocytes. In vivo experiments were performed in male KM mice. A mouse model of streptozotocin (STZ)-induced type 1 diabetes (T1D) was used, and lentiviral vectors were injected into the kidney cortex to overexpress FoxO1. A mouse podocyte cell line was treated with high concentrations of glucose and genetically modified using lentiviral vectors. We found aberrant mitochondrial morphology and reduced adenosine triphosphate production. These mitochondrial abnormalities were due to decreased mitophagy via reduced phosphatase/tensin homolog on chromosome 10-induced PINK1/Parkin-dependent signaling. FoxO1 upregulation and PINK1/Parkin pathway activation can individually restore injured podocytes in STZ-induced T1D mice. Our results link the antioxidative activity of FoxO1 with PINK1/Parkin-induced mitophagy, indicating a novel role of FoxO1 in diabetic nephropathy. 10.1210/en.2016-1970
Next-generation sequencing identifies TGF-β1-associated gene expression profiles in renal epithelial cells reiterated in human diabetic nephropathy. Brennan Eoin P,Morine Melissa J,Walsh David W,Roxburgh Sarah A,Lindenmeyer Maja T,Brazil Derek P,Gaora Peadar Ó,Roche Helen M,Sadlier Denise M,Cohen Clemens D, ,Godson Catherine,Martin Finian Biochimica et biophysica acta Transforming growth factor-beta (TGF-β1) is implicated in the onset and progression of renal fibrosis and diabetic nephropathy (DN), leading to a loss of epithelial characteristics of tubular cells. The transcriptional profile of renal tubular epithelial cells stimulated with TGF-β1 was assessed using RNA-Seq, with 2027 differentially expressed genes identified. Promoter analysis of transcription factor binding sites in the TGF-β1 responsive gene set predicted activation of multiple transcriptional networks, including NFκB. Comparison of RNA-Seq with microarray data from identical experimental conditions identified low abundance transcripts exclusive to RNA-Seq data. We compared these findings to human disease by analyzing transcriptomic data from renal biopsies of patients with DN versus control groups, identifying a shared subset of 179 regulated genes. ARK5, encoding an AMP-related kinase, and TGFBI - encoding transforming growth factor, beta-induced protein were induced by TGF-β1 and also upregulated in human DN. Suppression of ARK5 attenuated fibrotic responses of renal epithelia to TGF-β1 exposure; and silencing of TGFBI induced expression of the epithelial cell marker - E-cadherin. We identified low abundance transcripts in sequence data and validated expression levels of several transcripts (ANKRD56, ENTPD8) in tubular enriched kidney biopsies of DN patients versus living donors. In conclusion, we have defined a TGF-β1-driven pro-fibrotic signal in renal epithelial cells that is also evident in the DN renal transcriptome. 10.1016/j.bbadis.2012.01.008
Poly(Adenosine 5'-diphosphate-ribose) polymerase inhibition counteracts multiple manifestations of experimental type 1 diabetic nephropathy. Drel Viktor R,Xu Weizheng,Zhang Jie,Pavlov Ivan A,Shevalye Hanna,Slusher Barbara,Obrosova Irina G Endocrinology This study was aimed at evaluating the role for poly(ADP-ribose) polymerase (PARP) in early nephropathy associated with type 1 diabetes. Control and streptozotocin-diabetic rats were maintained with or without treatment with one of two structurally unrelated PARP inhibitors, 1,5-isoquinolinediol (ISO) and 10-(4-methyl-piperazin-1-ylmethyl)-2H-7-oxa-1,2-diaza-benzo[de] anthracen-3-one (GPI-15427), at 3 mg/kg(-1) x d(-1) ip and 30 mg/kg(-1) x d(-1), respectively, for 10 wk after the first 2 wk without treatment. PARP activity in the renal cortex was assessed by immunohistochemistry and Western blot analysis of poly(ADP-ribosyl)ated proteins. Variables of diabetic nephropathy in urine and renal cortex were evaluated by ELISA, Western blot analysis, immunohistochemistry, and colorimetry. Urinary albumin excretion was increased about 4-fold in diabetic rats, and this increase was prevented by ISO and GPI-15427. PARP inhibition counteracted diabetes-associated increase in poly(ADP-ribose) immunoreactivities in renal glomeruli and tubuli and poly(ADP-ribosyl)ated protein level. Renal concentrations of TGF-beta(1), vascular endothelial growth factor, endothelin-1, TNF-alpha, monocyte chemoattractant protein-1, lipid peroxidation products, and nitrotyrosine were increased in diabetic rats, and all these changes as well as an increase in urinary TNF-alpha excretion were completely or partially prevented by ISO and GPI-15427. PARP inhibition counteracted diabetes-induced up-regulation of endothelin (B) receptor, podocyte loss, accumulation of collagen-alpha1 (IY), periodic acid-Schiff-positive substances, fibronectin, and advanced glycation end-products in the renal cortex. In conclusion, PARP activation is implicated in multiple changes characteristic for early nephropathy associated with type 1 diabetes. These findings provide rationale for development and further studies of PARP inhibitors and PARP inhibitor-containing combination therapies. 10.1210/en.2009-0628
Nrf2 Deficiency Upregulates Intrarenal Angiotensin-Converting Enzyme-2 and Angiotensin 1-7 Receptor Expression and Attenuates Hypertension and Nephropathy in Diabetic Mice. Zhao Shuiling,Ghosh Anindya,Lo Chao-Sheng,Chenier Isabelle,Scholey James W,Filep Janos G,Ingelfinger Julie R,Zhang Shao-Ling,Chan John S D Endocrinology We investigated the role of nuclear factor erythroid 2-related factor 2 (Nrf2) in renin-angiotensin system (RAS) gene expression in renal proximal tubule cells (RPTCs) and in the development of systemic hypertension and kidney injury in diabetic Akita mice. We used adult male Akita Nrf2 knockout mice and Akita mice treated with trigonelline (an Nrf2 inhibitor) or oltipraz (an Nrf2 activator). We also examined rat immortalized RPTCs (IRPTCs) stably transfected with control plasmids or plasmids containing rat angiotensinogen (Agt), angiotensin-converting enzyme (ACE), angiotensin-converting enzyme-2 (Ace2), or angiotensin 1-7 (Ang 1-7) receptor (MasR) gene promoters. Genetic deletion of Nrf2 or pharmacological inhibition of Nrf2 in Akita mice attenuated hypertension, renal injury, tubulointerstitial fibrosis, and the urinary albumin/creatinine ratio. Furthermore, loss of Nrf2 upregulated RPTC Ace2 and MasR expression, increased urinary Ang 1-7 levels, and downregulated expression of Agt, ACE, and profibrotic genes in Akita mice. In cultured IRPTCs, Nrf2 small interfering RNA transfection or trigonelline treatment prevented high glucose stimulation of Nrf2 nuclear translocation, Agt, and ACE transcription with augmentation of Ace2 and MasR transcription, which was reversed by oltipraz. These data identify a mechanism, Nrf2-mediated stimulation of intrarenal RAS gene expression, by which chronic hyperglycemia induces hypertension and renal injury in diabetes. 10.1210/en.2017-00752
Mapping murine diabetic kidney disease using chemical exchange saturation transfer MRI. Wang Feng,Kopylov David,Zu Zhongliang,Takahashi Keiko,Wang Suwan,Quarles C Chad,Gore John C,Harris Raymond C,Takahashi Takamune Magnetic resonance in medicine PURPOSE:Diabetic nephropathy (DN) is the leading cause of renal failure; however, current clinical tests are insufficient for assessing this disease. DN is associated with changes in renal metabolites, so we evaluated the utility of chemical exchange saturation transfer (CEST) imaging to detect changes characteristic of this disease. METHODS:Sensitivity of CEST imaging at 7 Tesla to DN was evaluated by imaging diabetic mice [db/db, db/db endothelial nitric oxide synthase (eNOS)-/-] that show different levels of nephropathy as well as by longitudinal imaging (8 to 24 weeks). Nondiabetic (db/m) mice were used as controls. RESULTS:Compared with nondiabetic mice, the CEST contrasts of hydroxyl metabolites that correspond to glucose and glycogen were significantly increased in papilla (P), inner medulla (IM), and outer medulla (OM) in db/db and db/db eNOS-/- kidneys at 16 weeks. The db/db eNOS-/- mice that showed advanced nephropathy exhibited greater CEST effects in OM and significant CEST contrasts were also observed in cortex. Longitudinally, db/db mice exhibited progressive increases in hydroxyl signals in IM+P and OM from 12 to 24 weeks and an increase was also observed in cortex at 24 weeks. CONCLUSION:CEST MRI can be used to measure changes of hydroxyl metabolites in kidney during progression of DN. Magn Reson Med 76:1531-1541, 2016. © 2015 International Society for Magnetic Resonance in Medicine. 10.1002/mrm.26045
Vitamin D prevents podocyte injury via regulation of macrophage M1/M2 phenotype in diabetic nephropathy rats. Zhang Xiao-Liang,Guo Yin-Feng,Song Zhi-Xia,Zhou Min Endocrinology Increasing evidence suggests the heterogeneity of macrophage phenotype and function ultimately determines the outcome of diabetic nephropathy (DN). This study aimed to investigate the effects of vitamin D on macrophage M1/M2 phenotype and its role in preventing podocyte impairment in streptozotocin-induced DN rats. Calcitriol, a bioactive 1,25-dihydroxyvitamin D3, ameliorated proteinuria and renal damage as well as reversed the decline of both nephrin and podocin, crucial structural proteins in podocytes. DN rats showed increased infiltrating macrophages with M1 phenotype characterized by elevated expression of inducible nitric oxide synthase and TNF-α in glomeruli and interstitium, which were inhibited after calcitriol treatment. Interestingly, calcitriol promoted M2 macrophage activation with enhanced expression of CD163, arginase-1, and mannose receptor at week 18 but not at week 8 or 14. The ratio of CD163 to CD68, considered as the proportion of M2 macrophages, was about 2.9-fold higher at week 18 after calcitriol treatment. Furthermore, the protein expression of inducible nitric oxide synthase, a crucial marker of M1 macrophages, was negatively correlated with the expression of either nephrin or podocin, whereas CD163, indicating M2 macrophages, was positively correlated. In vitro, 1,25-dihydroxyvitamin D3 switched high-glucose-induced M1 macrophages toward an M2 phenotype in either U937-derived macrophages or RAW264.7 cells. Our results suggest that vitamin D not only reduces macrophage infiltration and inhibits M1 macrophage activation but also enhances M2 macrophage phenotype to protect against podocyte injury. 10.1210/en.2014-1020
Pathophysiology of obesity-related renal dysfunction contributes to diabetic nephropathy. Bayliss George,Weinrauch Larry A,D'Elia John A Current diabetes reports Recent studies have demonstrated the role of insulin resistance in renal injury related to obesity, with hyperfiltration leading to glomerulomegaly in a pattern similar to that found in diabetic nephropathy. Similarities in the histologic patterns of damage from obesity and diabetes point to overlapping mechanisms of injury. In this review, we will examine the hormonal mechanisms, signaling pathways and injury patterns in renal injury resulting from obesity and attempt to draw conclusions on the reasons for these similarities. 10.1007/s11892-012-0288-1
Expression and regulation of a novel identified TNFAIP8 family is associated with diabetic nephropathy. Zhang Shuya,Zhang Yan,Wei Xinbing,Zhen Junhui,Wang Ziying,Li Minyong,Miao Wei,Ding Hua,Du Pengchao,Zhang Wenchao,He Min,Yi Fan Biochimica et biophysica acta Tumor necrosis factor-α-inducible protein 8 (TNFAIP8) family are very recently identified proteins which share considerable sequence homology to regulate cellular and immune homeostasis. However, it is unknown whether TNFAIP8 family is expressed in the kidney and contributes to the regulation of renal functions. Therefore, the present study was designed to characterize the members of TNFAIP8 family in the kidney and to explore their possible roles in the development and progression of diabetic nephropathy. By RT-PCR and Western blot analyses, we found that all members of TNFAIP8 family were detected in the kidney. TNFAIP8 and TIPE2 expression was significantly increased in glomeruli from streptozotocin (STZ)-induced diabetic rats, and this upregulation was further confirmed in renal biopsies of diabetic patients. In in vitro study, TNFAIP8 was upregulated in response to high glucose in mesangial cells rather than podocytes. Moreover, a direct correlation was observed between expression of TNFAIP8 and mesangial cell proliferation and this regulation was associated with NADPH oxidase-mediated signaling pathway. However, we failed to observe the upregulation of TIPE2 in both mesangial cells and podocytes in response to high glucose. In conclusion, the present study addressed the role of TNFAIP8 family in diabetic nephropathy. These findings for the first time demonstrate that TNFAIP8 is one of critical components of a signal transduction pathway that links mesangial cell proliferation to diabetic renal injury. 10.1016/j.bbadis.2010.08.003
Blockade of cannabinoid receptor 1 improves insulin resistance, lipid metabolism, and diabetic nephropathy in db/db mice. Nam D H,Lee M H,Kim J E,Song H K,Kang Y S,Lee J E,Kim H W,Cha J J,Hyun Y Y,Kim S H,Han S Y,Han K H,Han J Y,Cha Dae Ryong Endocrinology The endocannabinoid system is important in the pathogenesis of obesity-related metabolic disorders. However, the effect of inhibiting the endocannabinoid system in type 2 diabetic nephropathy is unclear. Therefore, we examined the effect of the cannabinoid (CB)1 receptor antagonist, SR141716, on insulin resistance and diabetic nephropathy in db/db mice. Six-week-old db/db mice were treated with the CB1-specific antagonist SR141716 (10 mg/kg · d) for 3 months. Treatment with SR141716 significantly improved insulin resistance and lipid abnormalities. Concomitantly, CB1 antagonism improved cardiac functional and morphological abnormality, hepatic steatosis, and phenotypic changes of adipocytes into small differentiated forms, associated with increased adiponectin expression and decreased lipid hydroperoxide levels. CB1 receptor was overexpressed in diabetic kidneys, especially in podocytes. Treatment with the SR141716 markedly decreased urinary albumin excretion and mesangial expansion and suppressed profibrotic and proinflammatory cytokine synthesis. Furthermore, SR141716 improved renal lipid metabolism and decreased urinary 8-isoprostane levels, renal lipid hydroperoxide content, and renal lipid content. In cultured podocytes, high-glucose stimulation increased CB1 receptor expression, and SR141716 treatment abolished high-glucose-induced up-regulation of collagen and plasminogen activator inhibitor-1 synthesis. Additionally, knockdown of CB1 receptor expression by stealth small interfering RNA abolished high-glucose-induced sterol-regulatory element-binding protein-1 expression in podocytes. These findings suggest that CB1 blockade improves insulin resistance and protect against renal injury through both metabolic and antifibrotic effects in type 2 diabetic nephropathy. Targeting CB1 blockade could therefore provide a new therapeutic target to prevent type 2 diabetic nephropathy. 10.1210/en.2011-1423
Oxidative stress in diabetic nephropathy. Kashihara N,Haruna Y,Kondeti V K,Kanwar Y S Current medicinal chemistry Diabetic nephropathy is a leading cause of end-stage renal failure worldwide. Its morphologic characteristics include glomerular hypertrophy, basement membrane thickening, mesangial expansion, tubular atrophy, interstitial fibrosis and arteriolar thickening. All of these are part and parcel of microvascular complications of diabetes. A large body of evidence indicates that oxidative stress is the common denominator link for the major pathways involved in the development and progression of diabetic micro- as well as macro-vascular complications of diabetes. There are a number of macromolecules that have been implicated for increased generation of reactive oxygen species (ROS), such as, NAD(P)H oxidase, advanced glycation end products (AGE), defects in polyol pathway, uncoupled nitric oxide synthase (NOS) and mitochondrial respiratory chain via oxidative phosphorylation. Excess amounts of ROS modulate activation of protein kinase C, mitogen-activated protein kinases, and various cytokines and transcription factors which eventually cause increased expression of extracellular matrix (ECM) genes with progression to fibrosis and end stage renal disease. Activation of renin-angiotensin system (RAS) further worsens the renal injury induced by ROS in diabetic nephropathy. Buffering the generation of ROS may sound a promising therapeutic to ameliorate renal damage from diabetic nephropathy, however, various studies have demonstrated minimal reno-protection by these agents. Interruption in the RAS has yielded much better results in terms of reno-protection and progression of diabetic nephropathy. In this review various aspects of oxidative stress coupled with the damage induced by RAS are discussed with the anticipation to yield an impetus for designing new generation of specific antioxidants that are potentially more effective to reduce reno-vascular complications of diabetes. 10.2174/092986710793348581
Protein kinase C and protein kinase A are involved in the protection of recombinant human glucagon-like peptide-1 on glomeruli and tubules in diabetic rats. Journal of diabetes investigation AIMS/INTRODUCTION:Blockade or reversal the progression of diabetic nephropathy is a clinical challenge. The aim of the present study was to examine whether recombinant human glucagon-like peptide-1 (rhGLP-1) has an effect on alleviating urinary protein and urinary albumin levels in diabetic rats. MATERIALS AND METHODS:Streptozotocin-induced diabetes rats were treated with rhGLP-1 insulin and saline. Using immunostaining, hematoxylin-eosin, electron microscopy and periodic acid-Schiff staining to study the pathology of diabetic nephropathy, and we carried out quantitative reverse transcription polymerase chain reaction, western blot and immunohistochemistry to identify the differentially expressed proteins. The mechanism was studied through advanced glycation end-products-induced tubular epithelial cells. RESULTS:rhGLP-1 inhibits protein kinase C (PKC)-β, but increases protein kinase A (PKA), which reduces oxidative stress in glomeruli and in cultured glomerular microvascular endothelial cells. In tubules, rhGLP-1 increased the expression of two key proteins related to re-absorption - megalin and cubilin - which was accompanied by downregulation of PKC-β and upregulation of PKA. On human proximal tubular epithelial cells, rhGLP-1 enhanced the absorption of albumin, and this was blocked by a PKC activator or PKA inhibitor. CONCLUSIONS:These findings suggest that rhGLP-1 can reverse diabetic nephropathy by protecting both glomeruli and tubules by inhibiting PKC and activating PKA. 10.1111/jdi.12956
3,5-Diiodo-l-thyronine ameliorates diabetic nephropathy in streptozotocin-induced diabetic rats. Shang Guoguo,Gao Pan,Zhao Zhonghua,Chen Qi,Jiang Tao,Zhang Nong,Li Hui Biochimica et biophysica acta 3, 5-Diiodothyronine (T2), a natural metabolite of triiodothyronine (T3) from deiodination pathway, can mimic biologic effects of T3 without inducing thyrotoxic effects. Recent studies revealed T3 acted as a protective factor against diabetic nephropathy (DN). Nevertheless, little is known about the effect of T2 on DN. This study was designed to investigate whether and how T2 affects experimental models of DN in vivo and in vitro. Administration of T2 was found to prevent significant decrease in SIRT1 protein expression and activity as well as increases in blood glucose, urine albumin excretion, matrix expansion, transforming growth factor-β1 expression, fibronectin and type IV collagen deposition in the diabetic kidney. Concordantly, similar effects of T2 were exhibited in the cultured rat mesangial cells (RMC) exposed to high glucose and that could be abolished by a known SIRT1 inhibitor, sirtinol. Moreover, enhanced NF-κB acetylation and JNK phosphorylation present in both diabetic rats and high glucose-treated RMC were distinctly dampened by T2. Collectively, these results suggested that T2 was a protective agent against renal damage in diabetic nephropathy, whose action involved regulation of SIRT1. 10.1016/j.bbadis.2013.01.023
Insights into the Mechanisms Involved in the Expression and Regulation of Extracellular Matrix Proteins in Diabetic Nephropathy. Hu C,Sun L,Xiao L,Han Y,Fu X,Xiong X,Xu X,Liu Y,Yang S,Liu F,Kanwar Y S Current medicinal chemistry Diabetic Nephropathy (DN) is believed to be a major microvascular complication of diabetes. The hallmark of DN includes deposition of Extracellular Matrix (ECM) proteins, such as, collagen, laminin and fibronectin in the mesangium and renal tubulo-interstitium of the glomerulus and basement membranes. Such an increased expression of ECM leads to glomerular and tubular basement membranes thickening and increase of mesangial matrix, ultimately resulting in glomerulosclerosis and tubulointerstitial fibrosis. The characteristic morphologic glomerular mesangial lesion has been described as Kimmelstiel-Wilson nodule, and the process at times is referred to as diabetic nodular glomerulosclerosis. Thus, the accumulation of ECM proteins plays a critical role in the development of DN. The relevant mechanism(s) involved in the increased ECM expression and their regulation in the kidney in diabetic state has been extensively investigated and documented in the literature. Nevertheless, there are certain other mechanisms that may yet be conclusively defined. Recent studies demonstrated that some of the new signaling pathways or molecules including, Notch, Wnt, mTOR, TLRs and small GTPase may play a pivotal role in the modulation of ECM regulation and expression in DN. Such modulation could be operational for instance Notch through Notch1/Jagged1 signaling, Wnt by Wnt/β- catenin pathway and mTOR via PI3-K/Akt/mTOR signaling pathways. All these pathways may be critical in the modulation of ECM expression and tubulo-interstitial fibrosis. In addition, TLRs, mainly the TLR2 and TLR4, by TLR2- dependent and TGF-β-dependent conduits, may modulate ECM expression and generate a fibrogenic response. Small GTPase like Rho, Ras and Rab family by targeting relevant genes may also influence the accumulation of ECM proteins and renal fibrosis in hyperglycemic states. This review summarizes the recent information about the role and mechanisms by which these molecules and signaling pathways regulate ECM synthesis and its expression in high glucose ambience in vitro and in vivo states. The understanding of such signaling pathways and the molecules that influence expression, secretion and amassing of ECM may aid in developing strategies for the amelioration of diabetic nephropathy.
The effects of anti-inflammatory and anti-angiogenic DNA vaccination on diabetic nephropathy in rats. Celec Peter,Hodosy Július,Gardlík Roman,Behuliak Michal,Pálffy Roland,Pribula Marek,Jáni Peter,Turňa Ján,Sebeková Katarína Human gene therapy Inflammation and angiogenesis play a crucial role in the pathomechanism of diabetic nephropathy. Monocyte chemoattractant protein 1 (MCP) is a key regulator of the immune system in kidneys, and its inhibition with a dominant-negative mutant lacking the N-terminal amino acids 2-8 (7ND) reduces renal fibrosis. Angiomotin (Amot) is a novel angiogenesis modulator. We studied the effects of inhibition of Amot and MCP using DNA vaccination on incipient diabetic nephropathy in rats. Plasmid DNA (with either 7ND or human Amot) was electroporated twice into hind-limb muscles of rats with streptozotocin-induced diabetes mellitus. Sham-electroporated diabetic rats and healthy animals served as controls. After 4 months, renal histology and biochemical analyses were performed. In sham-electroporated diabetic rats, glomerular histology revealed pathological changes. 7ND and Amot treatments reduced glomerular hypertrophy and periodic acid-Schiff positivity. In both treated groups, the expression of profibrotic (transforming growth factor-β, collagen 1), proinflammatory (interleukin-6, tumor necrosis factor-α), and proangiogenic (vascular endothelial growth factor) genes in the renal cortex was lower than in the diabetic group without treatment. The mentioned renoprotective effects could be mediated via higher total antioxidant capacity and improved glycemic control. Anti-angiogenic and anti-inflammatory DNA vaccination ameliorates the progression of glomerular pathology in an animal model of diabetic nephropathy. 10.1089/hum.2011.030
Nrf2 ameliorates diabetic nephropathy progression by transcriptional repression of TGFβ1 through interactions with c-Jun and SP1. Gao Pan,Li Liliang,Ji Lili,Wei Yingze,Li Hui,Shang Guoguo,Zhao Zhonghua,Chen Qi,Jiang Tao,Zhang Nong Biochimica et biophysica acta Diabetic nephropathy (DN) is one of the major complications in diabetes patients. Reactive oxygen species (ROS) play key roles in DN progression. As a primary transcription factor, Nrf2 controls the antioxidant response to maintain cellular redox homeostasis. Herein we systemically examined the role of Nrf2 in DN progression and its regulatory mechanism in a mouse model bearing type II diabetes and in cultured human renal mesangial cells (HRMCs). We found that Nrf2 could ameliorate DN progression by transcriptional repression of TGFβ1 in vivo and in vitro. Moreover, Nrf2 bound to the specific region in TGFβ1 promoter by interactions with transcription factors c-Jun and SP1. Significant abolishment of Nrf2-mediated TGFβ1 transcriptional repression could be accomplished by knockdown of either c-Jun or SP1, and site-directed mutagenesis of c-Jun and SP1 binding sites in the TGFβ1 promoter specific region. Moreover, after interacting with c-Jun and SP1, Nrf2 inhibited c-Jun and SP1 activations, and thus reversed c-Jun- and SP1-promoted TGFβ1 transcription. In all, Nrf2 could slow down DN progression by repression of TGFβ1 in a c-Jun and SP1-dependent way. Our findings may provide novel clues for DN preventions and interventions in clinic. 10.1016/j.bbagrm.2014.06.018
MicroRNAs in Diabetic Nephropathy: From Biomarkers to Therapy. Simpson Kate,Wonnacott Alexa,Fraser Donald J,Bowen Timothy Current diabetes reports Recent estimates suggest that 1 in 12 of the global population suffers from diabetes mellitus. Approximately 40 % of those affected will go on to develop diabetes-related chronic kidney disease or diabetic nephropathy (DN). DN is a major cause of disability and premature death. Existing tests for prognostic purposes are limited and can be invasive, and interventions to delay progression are challenging. MicroRNAs (miRNAs) are a recently described class of molecular regulators found ubiquitously in human tissues and bodily fluids, where they are highly stable. Alterations in miRNA expression profiles have been observed in numerous diseases. Blood and tissue miRNAs are already established cancer biomarkers, and cardiovascular, metabolic and immune disease miRNA biomarkers are under development. Urinary miRNAs represent a potential novel source of non-invasive biomarkers for kidney diseases, including DN. In addition, recent data suggest that miRNAs may have therapeutic applications. Here, we review the utility of miRNAs as biomarkers for the early detection and progression of DN, assess emerging data on miRNAs implicated in DN pathology and discuss how the data from both fields may contribute to the development of novel therapeutic agents. 10.1007/s11892-016-0724-8
Novel curcumin analog C66 prevents diabetic nephropathy via JNK pathway with the involvement of p300/CBP-mediated histone acetylation. Wang Yangwei,Wang Yonggang,Luo Manyu,Wu Hao,Kong Lili,Xin Ying,Cui Wenpeng,Zhao Yunjie,Wang Jingying,Liang Guang,Miao Lining,Cai Lu Biochimica et biophysica acta Glomerulosclerosis and interstitial fibrosis represent the key events in development of diabetic nephropathy (DN), with connective tissue growth factor (CTGF), plasminogen activator inhibitor-1 (PAI-1) and fibronectin 1 (FN-1) playing important roles in these pathogenic processes. To investigate whether the plant metabolite curcumin, which exerts epigenetic modulatory properties when applied as a pharmacological agent, may prevent DN via inhibition of the JNK pathway and epigenetic histone acetylation, diabetic and age-matched non-diabetic control mice were administered a 3-month course of curcumin analogue (C66), c-Jun N-terminal kinase inhibitor (JNKi, sp600125), or vehicle alone. At treatment end, half of the mice were sacrificed for analysis and the other half were maintained without treatment for an additional 3 months. Renal JNK phosphorylation was found to be significantly increased in the vehicle-treated diabetic mice, but not the C66- and JNKi-treated diabetic mice, at both the 3-month and 6-month time points. C66 and JNKi treatment also significantly prevented diabetes-induced renal fibrosis and dysfunction. Diabetes-related increases in histone acetylation, histone acetyl transferases' (HATs) activity, and the p300/CBP HAT expression were also significantly attenuated by C66 or JNKi treatment. Chromatin immunoprecipitation assays showed that C66 and JNKi treatments decreased H3-lysine9/14-acetylation (H3K9/14Ac) level and p300/CBP occupancy at the CTGF, PAI-1 and FN-1 gene promoters. Thus, C66 may significantly and persistently prevent renal injury and dysfunction in diabetic mice via down-regulation of diabetes-related JNK activation and consequent suppression of the diabetes-related increases in HAT activity, p300/CBP expression, and histone acetylation. 10.1016/j.bbadis.2014.11.006
CXCL8 Antagonist Improves Diabetic Nephropathy in Male Mice With Diabetes and Attenuates High Glucose-Induced Mesangial Injury. Cui Siyuan,Zhu Yujie,Du Jianling,Khan Muhammad Noman,Wang Bing,Wei Jing,Cheng Jya-Wei,Gordon John R,Mu Yutian,Li Fang Endocrinology Inflammation is recognized as a crucial contribution to diabetic nephropathy (DN). CXCL8 binds to its CXC chemokine receptors (CXCR1 and CXCR2) for recruiting neutrophil infiltration and initiates tissue inflammation. Therefore, we explored the effect of CXCR1 and CXCR2 inhibition on DN. This was achieved by CXCL8(3-72)K11R/G31P (G31P), an antagonist of CXCL8 that has exhibited therapeutic efficacy in inflammatory diseases and malignancies. In this study, we found that renal leukocyte accumulation and rapid increases of CXCL8 occurred in high-fat diet/streptozocin-induced diabetic mice. G31P effectively reduced urine volume, urine albumin/creatinine ratio, blood urea nitrogen, and creatinine clearance rate in mice with diabetes. In addition, renal histopathologic changes including mesangial expansion, glomerulosclerosis, and extracellular matrix deposition were partially moderated in G31P-treated diabetic mice. Furthermore, G31P attenuated renal inflammation and renal fibrosis of diabetic mice by inhibiting proinflammatory and profibrotic elements. G31P also inhibited high glucose-induced inflammatory and fibrotic factor upregulation in human renal mesangial cells. At the molecular level, G31P inhibited activation of CXCR1/2 downstream signaling JAK2/STAT3 and ERK1/2 pathways in in vitro and in vivo experiments. Our results suggest blockade of CXCR1/2 by G31P could confer renoprotective effects that offer potential therapeutic opportunities in DN. 10.1210/en.2016-1781
Emerging roles for miRNAs in the development, diagnosis, and treatment of diabetic nephropathy. DiStefano Johanna K,Taila Matthew,Alvarez M Lucrecia Current diabetes reports Although the causes of diabetic nephropathy are not yet fully known, emerging evidence suggests a role for epigenetic factors in the development of the disease. In particular, microRNAs (miRNAs) are becoming recognized as important mediators of biological processes relevant to diabetic nephropathy. Until recently, investigations of miRNAs in the development of diabetic nephropathy have remained relatively limited; however, the number of reports identifying potential new candidates and mechanisms of impact is presently expanding at a rapid pace. This review seeks to summarize these recent findings, focusing on new candidates and/or novel mechanisms, including the intersection between genetic variation and miRNA function in modulating disease expression, emerging in the field. We also review the latest advances in the diagnostic and therapeutic potential of miRNAs in the treatment of diabetic nephropathy. 10.1007/s11892-013-0386-8
Design and optimization of crocetin loaded PLGA nanoparticles against diabetic nephropathy via suppression of inflammatory biomarkers: a formulation approach to preclinical study. Yang Xiaodong Drug delivery Diabetic nephropathy (DN) is a serious complication of diabetes mellitus whose expand process is linked with the fibrosis, renal hypertrophy and inflammation. The current study was to formulate and optimize the nano-formulation of crocetin (CT-PLGA-NPs) against Streptozotocin-induced renal nephropathy in rats. Double emulsion evaporation technique was used for the preparation of CT-PLGA-NPs. CT-PLGA-NPs were scrutinized for polydispersity index, size, gastric stability, entrapment, drug-loading capacity and drug release and preclinical study. Single intraperitoneal injection of streptozotocin (STZ) (55 mg/kg) and rats were divided into different group. Renal function and metabolic parameters of urine and serum were estimated. Fibrotic protein, renal pro-inflammatory cytokines and degree of renal damage expression were also determined. We also estimated the fibronectin, type IV collagen and transforming growth factor-β1 for a possible mechanism of action. Crocetin supplement (10 mg/kg) and CT-PLGA-NPs exhibited the accumulation of the drug in kidney and liver of diabetic rats. Crocetin reduced the BGL and enhanced plasma insulin and body weight. Dose dependent treatment of crocetin significantly ( < .001) down-regulated the expression of renal tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin (IL)-1β (IL-1β) and Monocyte Chemoattractant Protein-1 (MCP-1). Crocetin significantly ( < .001) altered the expression of fibronectin, type IV collagen, and transforming growth factor-β1 (TGF-1β). Crocetin significantly ( < .001) down-regulated the protein kinase C activity and the expression of nuclear factor κB (NF-κB) p65 activity and protein production in renal tissue. On the basis of the available result, we can conclude that nano-formulation of crocetin could attenuate the diabetic nephropathy via antifibrotic and anti-inflammatory effect. 10.1080/10717544.2019.1642417
The Role of Endoplasmic Reticulum Stress in Diabetic Nephropathy. Fan Ying,Lee Kyung,Wang Niansong,He John Cijiang Current diabetes reports PURPOSE OF REVIEW:Diabetic nephropathy (DN) has become the leading cause of end-stage renal disease (ESRD) worldwide. Accumulating evidence suggests that endoplasmic reticulum (ER) stress plays a major role in the development and progression of DN. Recent findings suggested that many attributes of DN, such as hyperglycemia, proteinuria, and increased advanced glycation end products and free fatty acids, can all trigger unfolded protein response (UPR) in kidney cells. Herein, we review the current knowledge on the role of ER stress in the setting of kidney injury with a specific emphasis on DN. RECENT FINDINGS:As maladaptive ER stress response caused by excessively prolonged UPR will eventually cause cell death and increase kidney injury, several ER stress inhibitors have been shown to improve DN in animal models, albeit blocking both adaptive and maladaptive UPR. More recently, reticulon-1A (RTN1A), an ER-associated protein, was shown to be increased in both human and mouse diabetic kidneys. Its expression correlates with the progression of DN, and its polymorphisms are associated with kidney disease in people with diabetes. Increased RTN1A expression heightened the ER stress response and renal cell apoptosis, and conversely reduced RTN1A in renal cells decreased apoptosis and ameliorated kidney injury and DN progression, suggesting that RTN1A may be a novel target to specifically restrain the maladaptive UPR. These findings suggest that ER stress response in renal cells is a key driver of progression of DN and that the inhibition of the unchecked ER stress response in DN, such as by inhibition of RTN1A function, may be a promising therapeutic approach against DN. 10.1007/s11892-017-0842-y
Inhibition of SREBP With Fatostatin Does Not Attenuate Early Diabetic Nephropathy in Male Mice. Van Krieken Richard,Marway Mandeep,Parthasarathy Pavithra,Mehta Neel,Ingram Alistar J,Gao Bo,Krepinsky Joan C Endocrinology Sterol regulatory element binding protein (SREBP) is an important potential mediator of kidney fibrosis and is known to be upregulated in diabetic nephropathy. We evaluated the effectiveness of SREBP inhibition as treatment of diabetic nephropathy. Type 1 diabetes was induced in uninephrectomized male CD1 mice with streptozotocin. The mice were treated with the SREBP inhibitor fatostatin for 12 weeks. At the endpoint, kidney function and pathologic findings were assessed. Fatostatin inhibited the increase of both isoforms of SREBP (types 1 and 2) in diabetic kidneys. Treatment attenuated basement membrane thickening but did not improve hyperfiltration, albuminuria, or kidney fibrosis in diabetic mice. The treatment of nondiabetic mice with fatostatin led to hyperfiltration and increased the glomerular volume to levels seen in diabetic mice. This was associated with increased renal inflammation and a trend toward increased renal fibrosis. Both in vivo and in cultured renal proximal tubular epithelial cells, fatostatin increased the expression of the proinflammatory cytokine monocyte chemoattractant protein-1. Thus, SREBP inhibition with fatostatin not only is ineffective in preventing diabetic nephropathy but also leads to kidney injury in nondiabetic mice. Further research on the efficacy of other SREBP inhibitors and the specific roles of SREBP-1 and SREBP-2 in the treatment and pathogenesis of diabetic nephropathy is needed. 10.1210/en.2018-00093
Caveolin-1 in the Pathogenesis of Diabetic Nephropathy: Potential Therapeutic Target? Van Krieken Richard,Krepinsky Joan C Current diabetes reports PURPOSE OF REVIEW:Diabetic nephropathy, a major microvascular complication of diabetes and the most common cause of end-stage renal disease, is characterized by prominent accumulation of extracellular matrix. The membrane microdomains caveolae, and their integral protein caveolin-1, play critical roles in the regulation of signal transduction. In this review we discuss current knowledge of the contribution of caveolin-1/caveolae to profibrotic signaling and the pathogenesis of diabetic kidney disease, and assess its potential as a therapeutic target. RECENT FINDINGS:Caveolin (cav)-1 is key to facilitating profibrotic signal transduction induced by several stimuli known to be pathogenic in diabetic nephropathy, including the most prominent factors hyperglycemia and angiotensin II. Phosphorylation of cav-1 on Y14 is an important regulator of these responses. In vivo studies support a pathogenic role for caveolae in the progression of diabetic nephropathy. Targeting caveolin-1/caveolae would enable inhibition of multiple profibrotic pathways, representing a novel and potentially potent therapeutic option for diabetic nephropathy. 10.1007/s11892-017-0844-9
AMPK signalling: Implications for podocyte biology in diabetic nephropathy. Szrejder Maria,Piwkowska Agnieszka Biology of the cell Diabetic nephropathy is a major long-term complication of diabetes mellitus and one of the most common causes of end-stage renal disease. Thickening of the glomerular basement membrane, glomerular cell hypertrophy and podocyte loss are among the main pathological changes that occur during diabetic nephropathy, resulting in proteinuria. Injury to podocytes, which are a crucial component of the glomerular filtration barrier, seems to play a key role in the development of diabetic nephropathy. Recent studies have suggested that dysregulation of AMP-activated kinase protein, which is an essential cellular energy sensor, may play a fundamental role in this process. The purpose of this review is to highlight the molecular mechanisms associated with AMP-activated protein kinase (AMPK) in podocytes that are involved in the pathogenesis of diabetic nephropathy. 10.1111/boc.201800077
Identification of key genes and pathways in diabetic nephropathy by bioinformatics analysis. Journal of diabetes investigation AIMS/INTRODUCTION:The aim of the present study was to identify candidate differentially expressed genes (DEGs) and pathways using bioinformatics analysis, and to improve our understanding of the cause and potential molecular events of diabetic nephropathy. MATERIALS AND METHODS:Two cohort profile datasets (GSE30528 and GSE33744) were integrated and used for deep analysis. We sorted DEGs and analyzed differential pathway enrichment. DEG-associated ingenuity pathway analysis was carried out. The screened gene expression feature was verified in the db/db mouse kidney cortex. Then, rat mesangial cells cultured with high-concentration glucose were used for verification. The target genes of transcriptional factor E26 transformation-specific-1 (ETS1) were predicted with online tools and validated using chromatin immunoprecipitation assay quantitative polymerase chain reaction. RESULTS:The two GSE datasets identified 89 shared DEGs; 51 were upregulated; and 38 were downregulated. Most of the DEGs were significantly enriched in cell adhesion, the plasma membrane, the extracellular matrix and the extracellular region. Quantitative reverse transcription polymerase chain reaction analysis validated the upregulated expression of Itgb2, Cd44, Sell, Fn1, Tgfbi and Il7r, and the downregulated expression of Igfbp2 and Cd55 in the db/db mouse kidney cortex. Chromatin immunoprecipitation assay quantitative polymerase chain reaction showed that Itgb2 was the target gene of transcription factor Ets1. ETS1 knockdown in rat mesangial cells decreased integrin subunit beta 2 expression. CONCLUSION:We found that EST1 functioned as an important transcription factor in diabetic nephropathy development through the promotion of integrin subunit beta 2 expression. EST1 might be a drug target for diabetic nephropathy treatment. 10.1111/jdi.12986