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PPDPF mitigates podocyte injury through promoting glycolysis in diabetic kidney disease

ABSTRACT: Podocyte injury is a critical early event in the progression of diabetic kidney disease (DKD), and metabolic reprogramming has emerged as a key determinant of podocyte dysfunction. 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. Notably, PPDPF expression was associated with podocyte loss, serum creatinine and glomerular filtration rate in patients with DKD. Thus, our findings identified PPDPF as a previously unrecognized guardian of podocyte glycolysis and suggest that targeting the PPDPF-dependent metabolic pathway may represent a promising therapeutic strategy for DKD.

ORGANISM(S): Homo sapiens

PROVIDER: GSE342320 | GEO | 2026/09/08

REPOSITORIES: GEO

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Project description:Diabetic kidney disease, a major microvascular complication of diabetes, is the primary cause of end-stage renal disease globally 1. Current treatments mainly target glycemic, blood pressure, and lipid control but often fail to prevent renal impairment. Early DKD is characterized by tubular damage, glomerular hypertrophy, thickening of the glomerular basement membrane, and loss of podocytes. Podocyte damage and loss are potentially significant in the pathogenesis of DKD. Hyperglycemia, a critical factor in podocyte injury, can contribute to the progression of DKD. Therefore, mitigating podocyte injury may be a crucial factor in the future management and alleviation of DKD. Chronic hyperglycemia leads to podocyte dysfunction through inflammation, oxidative stress, autophagy, and apoptosis. As is well known, the non-enzymatic glycation of proteins, leading to the formation of advanced glycation end-products (AGEs), constitutes a significant contributing factor to DKD. Notably, recent studies underscore the crucial role of O-linked-N-acetylglucosamine (O-GlcNAc) modification (also known as O-GlcNAcylation) in DKD progression. The hexosamine biosynthesis pathway (HBP) converts glucose to UDP-N -acetylglucosamine (UDP-GlcNAc), a substrate for O-GlcNAcylation, which is catalyzed by O-GlcNAc transferase (OGT) and removed by O-GlcNAcase (OGA). Aberrant O-GlcNAcylation is linked to renal fibrosis, inflammation, and apoptosis, which worsen diabetic kidney function. Elevated levels of O-GlcNAcylation have been observed in renal tissues of diabetic patients, indicating a potential link between hyperglycemia and dysregulated O-GlcNAc signaling. However, the exact molecular mechanisms of O-GlcNAcylation in DKD are not well understood. This study explores the changes in protein and glycosylated protein in podocytes after OGT knockdown to learn the molecular mechanisms of podocyte injury induced by high glucose (HG). A total of 128 up-regulated proteins and 45 down-regulated proteins in OGT knockdown group than in the control group were identified. Furthermore, 55 significantly changed glycosylation modification sites on 43 proteins were identified. To the best of our knowledge, this is the first study to conduct a global analysis of O-GlcNAcylation in podocytes.

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PPDPF mitigates podocyte injury through promoting glycolysis in diabetic kidney disease

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