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Dendritic cells are crucial for cardiovascular remodeling and modulate neutrophil gelatinase-associated lipocalin expression upon mineralocorticoid receptor activation. Araos Patricio,Prado Carolina,Lozano Mauricio,Figueroa Stefanny,Espinoza Alexandra,Berger Thorsten,Mak Tak W,Jaisser Frédéric,Pacheco Rodrigo,Michea Luis,Amador Cristián A Journal of hypertension BACKGROUND:Adaptive immunity is crucial in cardiovascular and renal inflammation/fibrosis upon hyperactivation of mineralocorticoid receptor. We have previously demonstrated that dendritic cells can respond to mineralocorticoid receptor activation, and the neutrophil gelatinase-associated lipocalin (NGAL) in dendritic cells is highly increased during aldosterone (Aldo)/mineralocorticoid receptor-dependent cardiovascular damage. However, the interrelationship among dendritic cells, target organs inflammation/fibrosis induced by mineralocorticoid receptor, and NGAL-dependence remains unknown. OBJECTIVE:We studied the role of dendritic cells in mineralocorticoid receptor-dependent tissue remodeling and whether NGAL can modulate the inflammatory response of dendritic cells after mineralocorticoid receptor activation. METHODS:Cardiovascular and renal remodeling induced by Aldo and high-salt diet [nephrectomy-Aldo-salt (NAS) model] were analyzed in CD11c.DOG mice, a model which allows dendritic cells ablation by using diphtheria toxin. In addition, in-vitro studies in NGAL-knock out dendritic cells were performed to determine the immunomodulatory role of NGAL upon Aldo treatment. RESULTS:The ablation of dendritic cells prevented the development of cardiac hypertrophy, perivascular fibrosis, and the overexpression of NGAL, brain natriuretic peptide, and two profibrotic factors induced by NAS: collagen 1A1 and connective tissue growth factor. We determined that dendritic cells were not required to prevent renal hypertrophy/fibrosis induced by NAS. Between different immune cells analyzed, we observed that NGAL abundance was higher in antigen-presenting cells, while in-vitro studies showed that mineralocorticoid receptor stimulation in dendritic cells favored NGAL and IL-23 expression (p19 and p40 subunits), which are involved in the development of fibrosis and the Th17-driven response, respectively. CONCLUSION:NGAL produced by dendritic cells may play a pivotal role in the activation of adaptive immunity that leads to cardiovascular fibrosis during mineralocorticoids excess. 10.1097/HJH.0000000000002067
Multiple apoptotic defects in hematopoietic cells from mice lacking lipocalin 24p3. Liu Zhuoming,Yang Amy,Wang Zhengqi,Bunting Kevin D,Davuluri Gangarao,Green Michael R,Devireddy Laxminarayana R The Journal of biological chemistry The lipocalin mouse 24p3 has been implicated in diverse physiological processes, including apoptosis, iron trafficking, development and innate immunity. Studies from our laboratory as well as others demonstrated the proapoptotic activity of 24p3 in a variety of cultured models. However, a general role for the lipocalin 24p3 in the hematopoietic system has not been tested in vivo. To study the role of 24p3, we derived 24p3 null mice and back-crossed them onto C57BL/6 and 129/SVE backgrounds. Homozygous 24p3(-/-) mice developed a progressive accumulation of lymphoid, myeloid, and erythroid cells, which was not due to enhanced hematopoiesis because competitive repopulation and recovery from myelosuppression were the same as for wild type. Instead, apoptotic defects were unique to many mature hematopoietic cell types, including neutrophils, cytokine-dependent mast cells, thymocytes, and erythroid cells. Thymocytes isolated from 24p3 null mice also displayed resistance to apoptosis-induced by dexamethasone. Bim response to various apoptotic stimuli was attenuated in 24p3(-/-) cells, thus explaining their resistance to the ensuing cell death. The results of these studies, in conjunction with those of previous studies, reveal 24p3 as a regulator of the hematopoietic compartment with important roles in normal physiology and disease progression. Interestingly, these functions are limited to relatively mature blood cell compartments. 10.1074/jbc.M110.216549
Resistance training decreases plasma levels of adipokines in postmenopausal women. Ward Liam J,Nilsson Sigrid,Hammar Mats,Lindh-Åstrand Lotta,Berin Emilia,Lindblom Hanna,Spetz Holm Anna-Clara,Rubér Marie,Li Wei Scientific reports Physical inactivity and the onset of menopause increase the risk of cardiovascular disease amongst postmenopausal women. We aim to investigate the effect of resistance training (RT) on plasma levels of selected cytokines, adipokines, myokines, and sex hormones in postmenopausal women with vasomotor symptoms. This was a sub-study of a randomised controlled trial investigating the effects of RT on vasomotor symptoms in postmenopausal women. Women were randomised to join a 15-week RT program (n = 26) or remain sedentary as control (n = 29). Venous blood samples were taken at week-0 and week-15 for all participants. Enzyme-linked immunosorbent assays and multiple bead assays were used to measure cytokines, adipokines, myokines, and sex hormones in plasma. Plasma measurements of 16 of 33 analytes were within detectable limits. After adjusting for good compliance in the RT group (58% of RT participants), after 15 weeks, significantly lower plasma levels of adiponectin (p < 0.001), lipocalin-2 (p < 0.01) and resistin (p = 0.04) were found. Comparing control and RT women, using change-over-time values, significant increases in median testosterone and sex hormone binding globulin levels were seen in RT women. RT intervention lowers the levels of adipokines, particularly adiponectin, in postmenopausal women with vasomotor symptoms. These results were secondary outcomes of a clinical trial, and further investigations in a larger cohort are essential with the additional control of diet control and body composition analyses. Nevertheless, our study shows RT may be a beneficial intervention in reducing inflammation amongst postmenopausal women. 10.1038/s41598-020-76901-w
Vitamin D promotes the cisplatin sensitivity of oral squamous cell carcinoma by inhibiting LCN2-modulated NF-κB pathway activation through RPS3. Huang Zixian,Zhang Yin,Li Haigang,Zhou Yufeng,Zhang Qianyu,Chen Rui,Jin Tingting,Hu Kaishun,Li Shihao,Wang Yan,Chen Weiliang,Huang Zhiquan Cell death & disease Chemoresistance is a major cause of cancer progression and the mortality of cancer patients. Developing a safe strategy for enhancing chemosensitivity is a challenge for biomedical science. Recent studies have suggested that vitamin D supplementation may decrease the risk of many cancers. However, the role of vitamin D in chemotherapy remains unknown. We found that vitamin D sensitised oral cancer cells to cisplatin and partially reversed cisplatin resistance. Using RNA-seq, we discovered that lipocalin 2 (LCN2) is an important mediator. Cisplatin enhanced the expression of LCN2 by decreasing methylation at the promoter, whereas vitamin D enhanced methylation and thereby inhibited the expression of LCN2. Overexpression of LCN2 increased cell survival and cisplatin resistance both in vitro and in vivo. High LCN2 expression was positively associated with differentiation, lymph node metastasis, and T staging and predicted a poor prognosis in oral squamous cell carcinoma (OSCC) patients. LCN2 was also associated with post-chemotherapy recurrence. Moreover, we found that LCN2 promoted the activation of NF-κB by binding to ribosomal protein S3 (RPS3) and enhanced the interaction between RPS3 and p65. Our study reveals that vitamin D can enhance cisplatin chemotherapy and suggests that vitamin D should be supplied during chemotherapy; however, more follow-up clinical studies are needed. 10.1038/s41419-019-2177-x
A Novel Biomarker Panel to Identify Steroid Resistance in Childhood Idiopathic Nephrotic Syndrome. Biomarker insights Idiopathic nephrotic syndrome (NS) is the most common glomerular disorder of childhood. Response to initial treatment with corticosteroids is an indicator of prognosis, as resistant patients often present more progressive disease. In this cross-sectional pilot study, we set out to discover a panel of noninvasive biomarkers that could distinguish steroid-resistant nephrotic syndrome (SRNS) from steroid-sensitive nephrotic syndrome (SSNS). Information gleaned from such a panel could yield more individualized treatment plans and prevent unnecessary steroid exposure in patients unlikely to respond. Urine was collected from 50 pediatric patients diagnosed with idiopathic NS at Cincinnati Children's Hospital Medical Center. Isobaric tags for relative and absolute quantitation (iTRAQ) was used to discover 13 proteins that were differentially expressed in SSNS vs SRNS in a small 5 × 5 discovery cohort. Suitable assays were found for 9 of the 13 markers identified by iTRAQ and were used in a 25 SRNS × 25 SSNS validation cohort. Vitamin D-binding protein (VDBP), alpha-1 acid glycoprotein 1 (AGP1), alpha-1 acid glycoprotein 2 (AGP2), alpha-1-B glycoprotein (A1BG), fetuin-A, prealbumin, thyroxine-binding globulin and hemopexin, and alpha-2 macroglobulin were measured and combined with urine neutrophil gelatinase-associated lipocalin (NGAL), which had been previously shown to distinguish patients with SRNS. Urinary VDBP, prealbumin, NGAL, fetuin-A, and AGP2 were found to be significantly elevated in SRNS using univariate analysis, with area under the receiver operating characteristic curves (AUCs) ranging from 0.65 to 0.81. Multivariate analysis revealed a panel of all 10 markers that yielded an AUC of 0.92 for identification of SRNS. A subset of 5 markers (including VDBP, NGAL, fetuin-A, prealbumin, and AGP2) showed significant associations with SRNS and yielded an AUC of 0.85. 10.1177/1177271917695832
Lipocalin 2 produces insulin resistance and can be upregulated by glucocorticoids in human adipose tissue. Kamble Prasad G,Pereira Maria J,Sidibeh Cherno O,Amini Sam,Sundbom Magnus,Börjesson Joey Lau,Eriksson Jan W Molecular and cellular endocrinology The adipokine lipocalin 2 is linked to obesity and metabolic disorders. However, its role in human adipose tissue glucose and lipid metabolism is not explored. Here we show that the synthetic glucocorticoid dexamethasone dose-dependently increased lipocalin 2 gene expression in subcutaneous and omental adipose tissue from pre-menopausal females, while it had no effect in post-menopausal females or in males. Subcutaneous adipose tissue from both genders treated with recombinant human lipocalin 2 showed a reduction in protein levels of GLUT1 and GLUT4 and in glucose uptake in isolated adipocytes. In subcutaneous adipose tissue, lipocalin 2 increased IL-6 gene expression whereas expression of PPARγ and adiponectin was reduced. Our findings suggest that lipocalin 2 can contribute to insulin resistance in human adipose tissue. In pre-menopausal females, it may partly mediate adverse metabolic effects exerted by glucocorticoid excess. 10.1016/j.mce.2016.03.011
NGAL distinguishes steroid sensitivity in idiopathic nephrotic syndrome. Bennett Michael R,Piyaphanee Nuntawan,Czech Kimberly,Mitsnefes Mark,Devarajan Prasad Pediatric nephrology (Berlin, Germany) BACKGROUND:Idiopathic nephrotic syndrome (NS) is the most common glomerular disorder of childhood. Invasive biopsy remains the diagnostic method of choice for NS. Prognosis correlates with steroid responsiveness, from sensitive (SSNS) to resistant (SRNS). Neutrophil gelatinase-associated lipocalin (NGAL) has been demonstrated to be a powerful risk marker of chronic kidney disease progression. We set out to determine if urine NGAL can distinguish between patients with SRNS, SSNS, and healthy controls. METHODS:Urine and clinical data were collected from patients at Cincinnati Children's Hospital who were recently diagnosed with active nephrotic syndrome as well as healthy controls. Participants included SRNS (n = 15), SSNS (n = 14), and healthy controls (n = 10). Urinary NGAL was measured by ELISA and normalized to creatinine. RESULTS:Median NGAL was significantly (p < 0.001) higher in SRNS (172.3 ng/ml, IQR 18.8-789) than both SSNS (6.3 ng/ml, IQR 4.9-9.9) and healthy controls (6.5 ng/ml, IQR 4.2-9.1). The area under the curve (AUC) for NGAL to distinguish SRNS from SSNS was 0.91 (p < 0.0001). NGAL levels demonstrated a significant negative correlation with glomerular filtration rate (r = -0.5, p < 0.001). Results did not change with NGAL corrected for urine creatinine and were independent of the degree of proteinuria. CONCLUSIONS:NGAL levels differentiate SSNS from SRNS and correlate with disease severity in SRNS. 10.1007/s00467-011-2075-7
Estrogen interacts with glucocorticoids in the regulation of lipocalin 2 expression in human adipose tissue. Reciprocal roles of estrogen receptor α and β in insulin resistance? Kamble Prasad G,Pereira Maria J,Almby Kristina,Eriksson Jan W Molecular and cellular endocrinology The adipokine lipocalin 2 (LCN2) is linked to insulin resistance. Its expression in human adipose tissue (AT) can be regulated in a sex-specific manner by a synthetic glucocorticoid, dexamethasone, suggesting an underlying role of sex steroids. We show that 17-β-estradiol (E2) dose-dependently increased LCN2 gene expression in subcutaneous AT from postmenopausal women. This was also seen in the presence of estrogen receptor (ER) α antagonist alone but not with ERβ antagonist, suggesting that E2 effects on LCN2 are mediated via ERβ pathway. Dexamethasone alone or E2+dexamethasone had no significant effect on LCN2. However, E2+dexamethasone increased LCN2 expression with ERα-blockade. Dexamethasone reduced ERα but increased ERβ expression. Dexamethasone can regulate LCN2 expression via inhibition of ERα and stimulation of ERβ and may contribute to the development of glucocorticoid-induced insulin resistance in human AT. In conclusion, ERβ and ERα pathways have opposite effects on LCN2 expression and they interact with glucocorticoid action. 10.1016/j.mce.2019.04.002
Urine Neutrophil Gelatinase Associated Lipocalin to Creatinine Ratio: A Novel Index for Steroid Response in Idiopathic Nephrotic Syndrome. Nickavar Azar,Safaeian Baranak,Sadeghi-Bojd Simin,Lahouti Harah dashti Arash Indian journal of pediatrics OBJECTIVE:To find the value of urine neutrophil gelatinase associated lipocalin (NGAL) in differentiating steroid response in children with idiopathic nephrotic syndrome (INS). METHODS:A total of 52 children with INS (n = 27, steroid resistant; n = 25, steroid responsive) aged 1-16 y, along with 18 healthy control children were enrolled in this study. Urine NGAL as well as urine protein, and serum creatinine were analyzed during active phase of INS. RESULTS:Serum creatinine (P 0.032), and urine NGAL/Cr (P 0.001) were significantly higher in steroid resistant than steroid sensitive patients. The optimal cutoff value for urine NGAL/Cr with the highest sensitivity and specificity was 0.46 ng/mg and cut off value of 0.01 and 1.15 ng/mg had maximum sensitivity and specificity, respectively. CONCLUSIONS:Urine NGAL/Cr could be considered as a marker of steroid resistance in children with idiopathic nephrotic syndrome. 10.1007/s12098-015-1809-0