Henagliflozin promotes mitophagy in renal tubular cells by activating AMPK/ULK1 to alleviate the progression of diabetic kidney disease.

BACKGROUND: Diabetic Kidney Disease (DKD) is a leading cause of end-stage kidney disease. As an inhibitor of sodium-glucose cotransporter 2 (SGLT2), Henagliflozin (Hen) has been shown to have significant renoprotection effects. However, the underlying mechanisms remain to be elucidated. In rescue experiments, HK2 cells were transfected with sh-AMPK plasmids and subsequently treated with HG and Hen for 24h. RESULTS: Renal injury and the inhibition of autophagy were both observed in patients with DKD and DKD mice. Consistent with these observations, HG-treated HK2 cells exhibited reduced cell viability and impaired autophagy activity. Hen treatment significantly ameliorated renal injury in DKD mice and enhanced cell viability in HG-treated HK2 cells. Furthermore, Hen exerts its protective effects by activating AMPK/ULK1-mediated mitophagy. Notably, AMPK downregulation effectively inhibited the activation of mitophagy induced by Hen treatment in HK2 cells. CONCLUSION: Hen exerts renoprotection effects by regulating AMPK/ULK1-dependent mitophagy, offering a novel therapeutic strategy for the clinical application of Hen.