MiR-33a Overexpression Exacerbates Diabetic Nephropathy Through Sirt6-dependent Notch Signaling

Abstract

Introduction. Diabetic nephropathy (DN) belongs to the major cause of end-stage kidney disease. We probed the functions of a microRNA miR-33a in inducing podocytes injury during childhood 
DN (CDN).

Methods. Kidney samples were collected from 20 children with DN. Matrix deposition and glomerular basement membranes thickness were examined by periodic acid-Schiff staining. Immunofluorescence staining was performed to assess kidney function-related proteins. MicroRNA (MiR)-33a mimic together with miR-33a inhibitor was transfected into podocytes for determining the roles of miR-33a. Glomerular podocyte apoptosis was determined by terminal deoxynucleotidyl transferase (TdT) dUTP Nick-End Labeling (TUNEL) staining along with flow cytometry.

Results. Down-regulation of Nephrin and Podocin and increased podocyte apoptosis rate were observed in the glomerulus of CDN as well as podocytes treated with high glucose. MiR-33a was up regulated in the glomeruli and glucose-treated podocytes. Injury in podocytes was aggravated with miR-33a elevation but alleviated with miR-33a inhibition. Moreover, the expression of Sirtuin 6 (Sirt6) was decreased while the levels of notch receptor 1 (Notch1) and notch receptor 4 (Notch4) were elevated in the glomerulus and glucose-treated podocytes. Decreased level of Sirt6 upon glucose treatment was abrogated by miR-33a inhibition, and the podocytes injury induced by glucose exposure was relieved by Sirt6 via Notch signaling.

Conclusion. These findings indicated that miR-33a promoted podocyte injury via targeting Sirt6-dependent Notch signaling in CDN, which might provide a novel sight for CDN treatment.

DOI: 10.52547/ijkd.7904