Ema_2025_Nephrol.Dial.Transplant__

BACKGROUND AND HYPOTHESIS: Ferroptosis is a key mechanism of tubular cell death in acute kidney injury (AKI), particularly in folic acid- and glycerol-induced models. Dipeptidyl peptidase 4 (DPP4) and sodium-glucose cotransporter 2 (SGLT2) inhibitors exhibit renoprotective effects beyond glucose lowering, and emerging evidence suggests both may suppress ferroptosis. We hypothesized that teneligliptin (TG) and empagliflozin (EMPA) protect tubular cells from ferroptosis-mediated injury by reducing lipid peroxidation. METHODS: HK-2 cells were pretreated with inhibitors of apoptosis (z-VAD-FMK), necroptosis (necrostatin-1s), or ferroptosis (ferrostatin-1), and then exposed to folic acid or myoglobin. The effects of TG on erastin-, folic acid-, and myoglobin-induced injury, and of EMPA on erastin- and myoglobin-induced injury, were evaluated using cell viability and lipid peroxidation assays. In vivo, TG was tested in folic acid- and glycerol-induced AKI models, and EMPA in the glycerol-induced AKI model. Renal function, tubular injury, inflammation, and glutathione peroxidase 4 (GPX4) expression were assessed. Localization of DPP4, NADPH oxidase 1 (NOX1), NOX4, and megalin in the kidney was analyzed by immunostaining. RESULTS: Ferrostatin-1, but not z-VAD-FMK or necrostatin-1s, prevented folic acid- and myoglobin-induced cell death in vitro. Both TG and EMPA significantly reduced erastin-induced cell death and lipid peroxidation. TG also attenuated cell death and lipid peroxidation in folic acid- and myoglobin-induced injury. EMPA improved viability and reduced lipid peroxidation in the myoglobin model. In vivo, TG improved renal function, reduced tubular damage and inflammation, and preserved GPX4 expression. EMPA showed similar protective effects in rhabdomyolysis-associated AKI. DPP4 co-localized with NOX4, but showed no co-localization with NOX1. TG treatment disrupted the co-localization of NOX4 with DPP4. CONCLUSION: TG and EMPA attenuate tubular cell death and kidney injury in ferroptosis-mediated AKI models, potentially through the reduction of lipid peroxidation. These findings highlight ferroptosis suppression as a potential mechanism underlying their renoprotective effects in AKI prevention.