Metformin inhibits high glucose-induced apoptosis of renal podocyte through regulating miR-34a/SIRT1 axis.

Abstract

Previous studies have reported SIRT1 was inversely modulated by miR-34a, However, mechanism of metformin (MFN)'srenal podocyte protection under high glucose (HG)conditions and the connection between miR-34a and SIRT1 expression in diabetic nephropathy (DN)remain unclear. We aimed to further elucidate the role of miR-34a in HG-treated podocytes in DN. A conditionally immortalized human podocyte cell line was cultivated in d-glucose (30 mM). Microarray and RT-qPCRrevealed that miR-34a was downregulated in HG-treatedpodocytes. Additionally, miR-34a levels increased in MFN-treated HG-induced podocytes. CCK-8assay, colony formation assay,flow cytometry,and Western blotdetection showed that HG treatment reduced cell viability and promoted via HG treatment, and MFN treatment reversed this phenotypic change. MiR-34a upregulation caused restored cell viability and suppressed cell apoptosis in HG-treated podocytes, and miR-34a downregulation led to damaged cell survival and induced apoptosis in MFN-administered and HG-treated podocytes. The dual luciferase reporter assay showed that SIRT1 3'-UTR was a direct miR-34a target. Further studies demonstrated an elevation in SIRT1 levels in HG-exposed podocytes, whereas MFN treatment decreased SIRT1 levels. In addition, miR-34a upregulation led to reduced SIRT1 expression, whereas miR-34a inhibition increased SIRT1 levels in cells. MFN-induced miR-34a suppresses podocyte apoptosis under HG conditions by acting on SIRT1. This study proposes a promising approach to interpret the mechanisms of action of the MFN-miR-34a axis involved in DN.