The sodium-glucose cotransporter 2 inhibitor empagliflozin reverses hyperglycemia-triggered vascular endothelial cell dysfunction by regulating mitochondria dynamics

INTRODUCTION: Hyperglycemia-induced endothelial injury is a major contributor to diabetic vasculopathy. While sodium-glucose transporter2 (SGLT2) in renal proximal tubules plays a critical role in diabetes, its expression and function in kidney endothelial cells, particularly regarding sex-specific disease progression, remain unclear. MATERIAL AND METHODS: SGLT2 expression in kidney endothelial cells was examined in male streptozotocin (STZ)-induced diabetic miceusing immunostaining. In human umbilical vein endothelial cells (HUVECs) treated with high glucose, we investigated the impact ofSGLT2 on mitochondrial dynamics following empagliflozin treatment. Molecular mechanisms were elucidated using qRT-PCR and Westernblot. Therapeutic efficacy was evaluated by histological analysis. RESULTS: SGLT2 was significantly upregulated in kidney endothelial cells of diabetic male mice. High glucose increased SGLT2 expressionin HUVECs, promoting mitochondrial fission and reducing fusion. Both SGLT2 siRNA knockdown and empagliflozin treatment markedlyenhanced mitochondrial fusion. Mechanistically, empagliflozin activated AMPK, increasing KLF4 expression and promoting mitochondrialfusion, thereby protecting against endothelial dysfunction. AMPK inhibition abrogated empagliflozin's protective effects in diabetic mice. CONCLUSIONS: SGLT2 critically regulates endothelial dysfunction under hyperglycemic conditions through the AMPK/KLF4-mitochondrialdynamics axis. Empagliflozin protects both proximal tubules and kidney endothelial cells in diabetes. Given accelerated diabetic kidneydisease progression in males, our male mouse model findings provide clinically relevant insights into sex-specific therapeutic responsesto SGLT2 inhibitors in diabetic vasculopathy.