Abstract

Podocyte injury plays a central role in the pathogenesis of diabetic nephropathy (DN). Protein tyrosine phosphatase receptor type O (PTPRO) has been implicated in glomerular disease, yet its specific role and regulatory mechanism in DN remain poorly understood. Here, we demonstrated that PTPRO expression was significantly downregulated in the glomeruli of DN mice and patients with DN, as well as in cultured podocytes exposed to diabetic stressors. Functional studies revealed that Ptpro knockdown induced podocyte injury, characterized by reduced Nephrin and Podocin expression, increased apoptosis, actin cytoskeleton disruption, enhanced migration, and reduced adhesion. Conversely, PTPRO overexpression ameliorated high glucose (HG)-induced podocyte damage. Mechanistically, PTPRO interacted with and dephosphorylated c-Abl, thereby suppressing the c-Abl/p53 signaling pathway. Pharmacological activation of c-Abl abolished the protective effects of PTPRO. Furthermore, we identified PTPRO as a direct transcriptional target of WT1, a podocyte master transcription factor downregulated in DN. WT1 overexpression restored PTPRO expression, suppressed c-Abl/p53 signaling, and ameliorated HG-induced podocyte injury in vitro. In vivo, podocyte-specific overexpression of WT1 via adeno-associated virus delivery in db/db mice attenuated proteinuria, glomerulosclerosis, and podocyte foot process effacement, accompanied by restored PTPRO expression and inhibition of the c-Abl/p53 pathway. Collectively, these findings establish that PTPRO functions downstream of WT1 to protect podocytes in DN by suppressing c-Abl/p53 signaling. Targeting the WT1-PTPRO-c-Abl-p53 axis may represent a novel therapeutic strategy for DN.