Branched-chain amino acids contribute to diabetic kidney disease progression via PKM2-mediated podocyte metabolic reprogramming and apoptosis.

Approximately 30-40% of patients with diabetes develop diabetic kidney disease (DKD). Identifying decisive factors for DKD initiation is crucial. Here, we observed that glomerular podocytes in male and female patients with DKD and db/db mice specifically displayed BCAA catabolic defects. Podocyte-specific PP2Cm (a key BCAA catabolism enzyme) knockout or exogenous BCAA supplementation induced DKD phenotypes including podocyte dysfunction/apoptosis, glomerular pathology, and proteinuria in high-fat (HF)-diet-fed male mice. Mechanistically, BCAAs promoted PKM2 depolymerization and inactivation in podocytes. Depolymerized PKM2 suppressed glucose oxidative phosphorylation (OXPHOS), diverting glucose metabolism towards serine biosynthesis and folate metabolism. Depolymerized PKM2 is also co-transported with DDIT3 into the nucleus, acting as a co-transcriptional factor to enhance DDIT3 transcriptional activity, which promotes Chac1 and Trib3 expression and directly inducing podocyte apoptosis. Thus, BCAA catabolic defects may be one of the missing factors that determine DKD initiation. Targeting BCAA catabolism or PKM2 activation is a promising DKD prevention strategy.