GSK3B variations influence renoprotective responses to dapagliflozin in diabetic kidney disease

Dapagliflozin shows variable renoprotective efficacy in patients with type 2 diabetic kidney disease (T2DKD). A retrospective clinical analysis confirmed marked interindividual variability in its urinary protein-lowering effects. To investigate the mechanism, drug affinity responsive target stability (DARTS) combined with quantitative proteomics was applied for target identification. Subsequent in vivo and in vitro validation suggested that GSK3β acts as a mediator of dapagliflozin-associated nephroprotection. Dapagliflozin directly bound and partially inhibited GSK3β, and GSK3β activity influenced podocyte protection. To translate findings into clinical relevance, a prospective trial was conducted. The GSK3B rs60393216 polymorphism was associated with urinary albumin-to-creatinine ratio (UACR) reduction after dapagliflozin therapy. These findings suggest that GSK3β contributes to the renoprotective effects of dapagliflozin and that GSK3B polymorphisms may influence therapeutic responses in T2DKD.