Exosomal lncRNA-PVT1 secreted from bone marrow mesenchymal stem cells attenuates diabetic nephropathy by targeting miR-423-5p/Sirt1/HIF-1α signaling

Abstract

Introduction:

Diabetic nephropathy (DN) is a major cause of end-stage renal disease (ESRD), yet effective disease-modifying therapies remain limited. Emerging evidence implicates long non-coding RNAs (lncRNAs) in the pathogenesis of DN, but the functional relevance of plasmacytoma variant translocation 1 (PVT1) and its downstream mechanism remain poorly defined. Here, we investigated whether PVT1 protects against diabetic renal injury through the miR-423-5p/Sirt1/HIF-1α axis.

Materials and Methods:

DN was modeled in db/db mice and high glucose-treated renal cells. PVT1 was overexpressed or inhibited, and miR-423-5p was modulated using specific mimics or inhibitors. Renal function, histopathology, and fibrotic changes were evaluated by biochemical assays, histological staining, qRT-PCR, and Western blotting. The expression of PVT1, miR-423-5p, Sirt1, HIF-1α, and fibrosis-related markers was determined to define their regulatory relationships.

Results:

PVT1 was dysregulated in diabetic kidneys and high glucose-exposed renal cells. In db/db mice, PVT1 overexpression significantly improved renal function, as evidenced by reduced 24-h urinary protein excretion, serum creatinine, and blood urea nitrogen, and attenuated pathological renal injury. PVT1 also suppressed extracellular matrix accumulation and fibrosis-related signaling, including α-SMA, collagen I, collagen IV, fibronectin, and TGF-β1. Mechanistically, PVT1 acted through the miR-423-5p/Sirt1/HIF-1α pathway, and inhibition of miR-423-5p abrogated the renoprotective effects of PVT1. These findings support a functional model in which PVT1 alleviates diabetic renal injury by repressing miR-423-5p and restoring Sirt1-dependent signaling.

Conclusions:

PVT1 mitigates DN progression by targeting the miR-423-5p/Sirt1/HIF-1α axis and limiting renal fibrosis. This lncRNA-centered regulatory pathway may represent a promising therapeutic target for diabetic kidney disease.