Phosphoglycerate kinase 1 contributes to diabetic kidney disease through enzyme-dependent and independent manners

Diabetic kidney disease (DKD) is characterized by abnormal metabolic profiles. Metabolomics revealed increased serum levels of 3-phosphoglycerate (3-PG) in DKD patients. The protein expression of phosphoglycerate kinase 1 (PGK1), a key rate-limiting enzyme for 3-PG synthesis, was concomitantly upregulated in DKD patients and mice. The development of DKD was significantly mitigated by renal tubular epithelial cell-specific knockout of PGK1 and robustly worsened by PGK1 overexpression. Mechanistically, PGK1-dependent enzymatic production of 3-PG facilitated DKD through inhibiting GPX1 to activate the NLRP3 inflammasome. PGK1 promoted UNC5CL-mediated inflammation by binding with aldehyde dehydrogenase-1 L1 (Aldh1l1) through its non-enzymatic activity. The transcription factor paired box protein 5 (PAX5) mediated the upregulation of PGK1 in DKD. High-throughput screening revealed that C-16 from ChemDiv, the natural product lirinidine, and the FDA-approved Oxantel Pamoate were potent PGK1 antagonists and efficaciously prevented DKD. Overall, blocking PGK1 may be a promising avenue for DKD management. Here, we had put the raw blots (unadjusted and uncropped blots with size markers) and raw stained images for cells in Mendeley.