PPDPF mitigates podocyte injury through promoting glycolysis in diabetic kidney disease

Although podocytes rely predominantly on glycolysis to maintain their structural and functional integrity, the molecular regulators controlling glycolytic flux in podocytes during DKD remain incompletely understood. Here, we demonstrated that pancreatic progenitor cell differentiation and proliferation factor (PPDPF) was significantly reduced in podocytes from both DKD patients and diabetic mice.

Podocyte-specific deletion of PPDPF in mice aggravated albuminuria, glomerular injury, and podocyte injury under diabetic conditions. However, overexpression of PPDPF ameliorated cytoskeletal disorganization and foot process effacement through increasing glycolytic flux and ATP production. Mechanistically, PPDPF competitively bound to WW Domain-containing E3 Ubiquitin Protein Ligase 1 (WWP1) and suppressed WWP1-mediated ubiquitination and degradation of CCCTC-binding factor (CTCF), thereby sustaining phosphoglycerate mutase 1 (PGAM1) transcription and promoting podocyte glycolysis.