SGLT2 Inhibitors Reduce the Progression from AKI to CKD by Inhibiting Ferroptosis

Background: Sodium-glucose cotransporter 2 (SGLT2) inhibitors are known for their renoprotective effects in diabetes but their role in acute kidney injury (AKI) remains less explored. This study evaluates the impact of the SGLT2 inhibitor luseogliflozin on the transition from AKI to chronic kidney disease (CKD) in a mouse model, focusing on its anti-ferroptotic effects. Methods: Using C57BL/6 mice, ischemic reperfusion (I/R injury was induced via bilateral renal pedicle clamping. Luseogliflozin or vehicle was administered for 2 weeks prior to and until sacrifice after the I/R injury. Renal function was assessed by serum creatinine and urea levels, and tissue damage by histological scoring. Renal fibrosis was assessed by Sirius Red Staining and Masson trichrome Staining. Metabolic shifts, oxidative stress and ferroptosis were evaluated through biochemical assays, histology, western blotting, and metabolomic analysis. Results: Luseogliflozin significantly reduced markers of renal dysfunction and histological damage in the early post-ischemic phase. It also attenuated renal fibrosis and inflammation markers at one-week post-injury. Metabolic analysis revealed an inhibition of the glycolytic pathway and an enhancement of fatty acid oxidation and mitochondrial function. Key signaling molecules such as AMPK and Nrf2 were activated, correlating with reduced oxidative stress and suppressed ferroptosis. Conclusion: Luseogliflozin mitigates the progression from AKI to CKD by modulating metabolic pathways and reducing oxidative stress and ferroptosis. This study suggests a potential therapeutic role for SGLT2 inhibitors in the management of AKI, advocating for further clinical investigation. Funding: Commercial Support - Taisho Pharmaceutical Co