MicroRNA-451 Modulates Autophagy-Related Signaling with Relevance to Renal Fibrosis in an Accelerated Mouse Model of Diabetic Kidney Disease

TL;DR

This study shows that increasing miR-451 in mice with diabetic kidney disease reduces kidney fibrosis and changes autophagy signaling, even without improving blood sugar levels.

Contribution

The study demonstrates that miR-451 reduces renal fibrosis and modulates autophagy in diabetic kidney disease independently of metabolic control.

Findings

miR-451 overexpression significantly reduced YWHAZ and mTOR protein levels in diabetic mice.

miR-451 treatment attenuated glomerular fibrosis in both wild-type and diabetic mice.

miR-451 increased autophagy-related proteins ATG101 and Beclin-1 while reducing the LC3-II/I ratio.

Abstract

Background: Diabetic nephropathy is characterized by metabolic dysregulation, renal fibrosis, and impaired autophagy. MicroRNA-451 (miR-451) has been implicated in metabolic and stress-response pathways, but its role in diabetic kidney disease remains unclear. This study examined the effects of systemic miR-451 overexpression on renal injury and autophagy in BTBR ob/ob mice. Methods: Wild-type (WT) and BTBR ob/ob (OB) mice were treated with miR-451 mimics. Body weight, blood glucose, and urine albumin were assessed for three consecutive weeks. Renal miR-451 expression was measured by qRT-PCR, while protein levels of YWHAZ, mTOR, and autophagy markers were analyzed by Western blotting. Renal fibrosis was evaluated using Masson’s trichrome staining. Results: OB mice exhibited increased body weight, hyperglycemia, and albuminuria compared with WT controls. miR-451 treatment resulted in robust renal overexpression of miR-451 in OB treated mice (8.4-fold, p = 0.039) but did not normalize metabolic parameters. miR-451 overexpression significantly reduced renal expression of YWHAZ and mTOR. Histological analysis revealed increased glomerular fibrosis in OB mice, which was significantly attenuated following miR-451 treatment in WT-treated and OB-treated mice. In addition, miR-451 treatment increased expression of autophagy-related proteins ATG101 and Beclin-1 and reduced the LC3-II/I ratio, indicating altered autophagic signaling. Conclusions: miR-451 overexpression attenuates renal fibrosis and modulates autophagy-associated pathways in diabetic kidney disease, independent of metabolic control, highlighting miR-451 as a potential therapeutic target for diabetic kidney disease.

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