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Rs12976445 Polymorphism is Associated with Risk of Diabetic Nephropathy Through Modulating Expression of MicroRNA-125 and Interleukin-6R.

ABSTRACT: Diabetic nephropathy (DN) is one of the most significant long-term complications of diabetes mellitus (DM), and it is a primary risk factor for end-stage renal disease. MicroRNAs (miRNAs) play important roles in regulating the expression of genes, including interleukin-6R (IL-6R), which has been reported to be involved in the development of DNDN. The aim of this study was to identify the dysregulation of miRNA and its target responsible for the development of DN in DM.We collected the kidney tissues from patients with DN (N=36) and control patients (N=28), and performed real-time PCR and Western blot analysis to determine the expression of IL-6R. Computational analysis and luciferase assay were used to identify the miRNA that regulates IL-6R. To explore the association between rs12976445 polymorphism and risk of DN, we enrolled 594 DM patients with (N=282) or without DN (N=312), and studied the association between a variant in miR-125a and risk of DN in DM.The expression of IL-6R was barely detected in the control groups, while in the DN group, the IL-6R was clearly detectable. Next, miR-125a was identified as a regulator of IL-6R by using informatics analysis and luciferase assay. A single-nucleotide polymorphism (rs12976445) in pri-miR-125a has been shown to compromise the mature processing of miR-125a, and we showed that the expression levels of miR-125a was comparable between individuals carrying TT and CT, and when combined into 1 group, the miR-125a expression was approximately 3 times lower than in the CC group. We found significant differences regarding rs12976445 genotype distribution between the DN and the control (OR=1.45, 95% C.I.=1.02-2.08, p<0.05) with the possible confounding factors adjusted for by using logistic regression analysis.We identified miR-125a as a direct regulator of IL-6R, and the genotype of rs12976445 might be a novel predictor of the development of DN in DM.

SUBMITTER: Li C

PROVIDER: S-EPMC4648103 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Rs12976445 Polymorphism is Associated with Risk of Diabetic Nephropathy Through Modulating Expression of MicroRNA-125 and Interleukin-6R.

Li Cunjie C Lei Ting T

Medical science monitor : international medical journal of experimental and clinical research 20151113

<h4>Background</h4>Diabetic nephropathy (DN) is one of the most significant long-term complications of diabetes mellitus (DM), and it is a primary risk factor for end-stage renal disease. MicroRNAs (miRNAs) play important roles in regulating the expression of genes, including interleukin-6R (IL-6R), which has been reported to be involved in the development of DNDN. The aim of this study was to identify the dysregulation of miRNA and its target responsible for the development of DN in DM.<h4>Mate ...[more]

PMID: 26563755

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Project description:Diabetic nephropathy (DN) is one of the most lethal complications of diabetes mellitus with metabolic disorders and chronic inflammation. Although the cytokine IL-22 was initially implicated in the pathogenesis of chronic inflammatory diseases, recent studies suggested that IL-22 could suppress inflammatory responses and alleviate tissue injury. Herein, we examined the role of IL-22 in DN. We found that serum levels of IL-22 were significantly downregulated in both patients and mice with DN. The expression of IL-22 was further decreased with the progression of DN, whereas IL-22 gene therapy significantly ameliorated renal injury and mesangial matrix expansion in mice with established nephropathy. IL-22 could also markedly reduce high glucose-induced and TGF-?1-induced overexpression of fibronectin and collagen IV in mouse renal glomerular mesangial cells in a dose-dependent manner, suggesting the potential role of IL-22 to inhibit the overproduction of ECM in vitro. Simultaneously, IL-22 gene therapy drastically alleviated renal fibrosis and proteinuria excretion in DN. In addition, IL-22 gene therapy markedly attenuated hyperglycemia and metabolic disorders in streptozotocin-induced experimental diabetic mice. Notably, IL-22 drastically reversed renal activation of NLRP3, cleavage of caspase-1, and the maturation of IL-1? in DN, suggesting unexpected anti-inflammatory function of IL-22 via suppressing the activation of NLRP3 inflammasome in vivo. Moreover, IL-22 markedly downregulated high glucose-induced activation of NLRP3 inflammasome in renal mesangial cells in a dose-dependent manner, indicating that the effects of IL-22 on NLRP3 inflammasome activation was independent of improved glycemic control. These results suggested that nephroprotection by IL-22 in DN was most likely associated with reduced activation of NLRP3 inflammasome. In conclusion, our finding demonstrated that IL-22 could exert favorable effects on DN via simultaneously alleviating systemic metabolic syndrome and downregulating renal NLRP3/caspase-1/IL-1? pathway, suggesting that IL-22 might have therapeutic potential for the treatment of DN.

Dataset Information

Rs12976445 Polymorphism is Associated with Risk of Diabetic Nephropathy Through Modulating Expression of MicroRNA-125 and Interleukin-6R.

Publications

Rs12976445 Polymorphism is Associated with Risk of Diabetic Nephropathy Through Modulating Expression of MicroRNA-125 and Interleukin-6R.

Similar Datasets

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