PTBP3 promotes diabetic nephropathy via Smad3-dependent podocyte-mesenchymal transition

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease (ESRD) worldwide, yet effective therapeutic targets remain limited. Podocyte injury and podocyte to mesenchymal transition represent critical pathological events driving renal fibrosis and progressive dysfunction in DN.

Through integrated transcriptomic data from public databases, we discovered that the RNA-binding protein PTBP3 is aberrantly elevated in DN. PTBP3 upregulation was validated in renal tissues from streptozotocin (STZ)-induced diabetic mice and in high glucose (HG) challenged podocytes, suggesting its potential involvement in DN pathogenesis. In PTBP3 knockdown mice, STZ-induced 24 h urinary protein, serum creatinine and blood urea nitrogen were significantly attenuated. Histological analyses revealed ameliorated glomerular hypertrophy and mesangial expansion, and reduced renal fibrosis upon PTBP3 knockdown. In addition, the results showed that the PTBP3 expression in glomeruli of diabetic mice was increased and PTBP3 silencing inhibited the EMT of podocytes in diabetic mice, which was accompanied with the decreased expression of SMAD3. This was evidenced by the restored expression of E-cadherin and the reduced expression of N-cadherin, vimentin, and fibronectin. The results from culture podocytes showed similar results. Mechanistically, the dual-luciferase and RNA immunoprecipitation assays demonstrated that PTBP3 interacted with the 3'-UTR of SMAD3 mRNA to facilitate its stabilization and increase its total protein and subsequent phosphorylation levels.

Notably, PTBP3 knockdown ameliorated renal fibrosis and preserved renal function, underscoring the therapeutic potential of targeting podocyte epithelial-mesenchymal transition in DN.