Fig. 8: The role of podocytes BCAAs catabolic defects upon DKD progression.

Glomerular podocytes in male and female patients with DKD and db/db mice specifically display BCAA catabolic defects. BCAA catabolic defects contribute to DKD development by inducing renal podocyte metabolic remodeling and apoptosis. BCAA catabolic defects result in podocyte PKM2 depolymerization and inactivation, which inhibits glucose OXPHOS and promotes a shift in glucose metabolism to serine biosynthesis and folate metabolism. BCAA promotes PKM2-DDIT3 binding, nuclear co-transportation, and regulates DDIT3 transcriptional activation of Chac1 and Trib3, which induce podocyte apoptosis.