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High glucose induces renal tubular epithelial injury via Sirt1/NF-kappaB/microR-29/Keap1 signal pathway.
- Source :
-
Journal of translational medicine [J Transl Med] 2015 Nov 09; Vol. 13, pp. 352. Date of Electronic Publication: 2015 Nov 09. - Publication Year :
- 2015
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Abstract
- Objective: Diabetic 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.<br />Methods: An 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.<br />Results: In 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.<br />Conclusion: High glucose induces renal tubular epithelial injury via Sirt1/NF-κB/microR-29/Keap1 signal pathway.
- Subjects :
- 3' Untranslated Regions
Animals
Cell Survival
Chromatin Immunoprecipitation
Creatinine blood
Diabetes Mellitus, Experimental metabolism
Diabetes Mellitus, Experimental pathology
Diabetic Nephropathies metabolism
Disease Models, Animal
Kelch-Like ECH-Associated Protein 1
Kidney Tubules cytology
Male
NF-E2-Related Factor 2 metabolism
Neoplasm Proteins metabolism
Nucleocytoplasmic Transport Proteins metabolism
Rats
Rats, Wistar
Signal Transduction
Ubiquitination
Epithelial Cells metabolism
Glucose metabolism
Intracellular Signaling Peptides and Proteins metabolism
Kidney Tubules pathology
MicroRNAs metabolism
NF-kappa B metabolism
Sirtuin 1 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1479-5876
- Volume :
- 13
- Database :
- MEDLINE
- Journal :
- Journal of translational medicine
- Publication Type :
- Academic Journal
- Accession number :
- 26552447
- Full Text :
- https://doi.org/10.1186/s12967-015-0710-y