Abstract
ObjectiveDiabetic nephropathy (DN) is a serious complication that commonly confronted by diabetic patients. A common theory for the pathogenesis of this renal dysfunction in diabetes is cell injury, inflammation as well as oxidative stress. In this content, the detailed molecular mechanism underlying high glucose induced renal tubular epithelial injury was elaborated.MethodsAn in vivo rat model of diabetes by injecting streptozotocin (STZ) and an in vitro high glucose incubated renal tubular epithelial cell (HK-2) model were used. Expression levels of Keap1, nuclear Nrf2 and p65 were determined by western blotting. Level of microR-29 (miR-29) was assessed using quantitative RT-PCR. Combination of p65 and miR-29 promotor was assessed using chromatin immunoprecipitation. Keap1 3′-UTR activity was detected using luciferase reporter gene assay. Cell viability was determined using MTT assay.ResultsIn diabetic rat, miR-29 was downregulated and its expression is negatively correlated with both of serum creatinine and creatinine clearance. In high glucose incubated HK-2 cell, deacetylases activity of Sirt1 was attenuated that leads to decreased activity of nuclear factor kappa B (NF-κB). NF-κB was demonstrated to regulate miR-29 expression by directly binding to its promotor. The data of luciferase assay showed that miR-29 directly targets to Keap1 mRNA. While high glucose induced down regulation of miR-29 contributed to enhancement of Keap1 expression that finally reduced Nrf2 content by ubiquitinating Nrf2. Additionally, overexpression of miR-29 effectively relieved high glucose-reduced cell viability.ConclusionHigh glucose induces renal tubular epithelial injury via Sirt1/NF-κB/microR-29/Keap1 signal pathway.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-015-0710-y) contains supplementary material, which is available to authorized users.
Highlights
Diabetes mellitus is a common metabolic disorder which is associated with chronic complications such as angiopathy, retinopathy, and peripheral neuropathy
The correlation analysis demonstrated that abnormal miR29 expression is negatively related to serum creatinine (Spearman correlation is −0.96, P = 0.000; Fig. 1d) and creatinine clearance (Spearman correlation is −0.93, P = 0.000; Fig. 1e)
High glucose promotes ubiquitination of Nrf2 via miR‐29/ Keap1 axis To determine the downstream molecule of miR-29/ Keap1 axis, we examined Nrf2, a nuclear transcriptional factor that commonly activated by Keap1, in 45 mM high glucose-triggered HK-2miR−29 mimic cell
Summary
Diabetes mellitus is a common metabolic disorder which is associated with chronic complications such as angiopathy, retinopathy, and peripheral neuropathy. It was recognized that diabetes can lead to nephropathy. Studies in experimental models and in patients observed structural abnormalities in vascular and glomerular [1]. High glucose induced inflammatory response as well as activated inflammation related signal pathway. A class III histone deacetylase, is recognized as an important regulator in many high glucoserelated inflammatory diseases [4]. Sirt activator blunting pro-inflammatory pathways in mice fed a high fat, high calorie diet [5]. Sirt and its modulation of the acetylation status of the p65 subunit of nuclear factor kappa B (NF-κB) play an important role in regulating the inflammatory and apoptotic responses
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