1376-P: The Efficacy of Dapagliflozin Is Heterogeneous across Different Etiologies of AKI and AKI-to-CKD Transition

Introduction and Objective: There is a persistent lack of specific therapies targeting both acute kidney injury and the subsequent AKI-to-CKD transition. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) exhibit reno-protective effects, yet their impact on AKI-to-CKD transition across different etiologies remains unclear. This study investigated the effects of dapagliflozin (DAPA) on AKI and the subsequent AKI-to-CKD transition induced by unilateral ischemia-reperfusion injury (UIRI) and cisplatin. Methods: C57BL/6J mice were subjected to UIRI (28min) or cisplatin (15 mg/kg for AKI,10 mg/kg repeted doses for CKD). DAPA (10 mg/kg/day) or vehicle was administered via oral gavage starting 14 days prior to model establishment. Renal function (SCr, BUN, UACR) and pathology (PAS, Masson) were analyzed. Results: In UIRI-induced AKI, DAPA did not significantly alter SCr or BUN (P > 0.05) but significantly downregulated kidney mRNA levels of F4/80, Tgf-β1, and Tnf-α (P < 0.05). In the UIRI AKI-to-CKD model, DAPA significantly reduced SCr, BUN, and UACR (P < 0.05). Histological analysis showed significant recovery of tubular structure and reduced fibrosis (P < 0.05). However, in cisplatin-induced models, DAPA failed to improve renal function in both AKI (P > 0.05) and AKI-to-CKD transition (P > 0.05). Conclusion: The renal protective effect of DAPA exhibits selectivity for specific pathological mechanisms. It may be particularly applicable to kidney injury and chronic progression driven primarily by ischemia/hypoxia, energy metabolism disorders, and hemodynamic abnormalities, whereas its protective effect appears less pronounced in injuries centered on direct cytotoxicity and intense acute inflammatory storms.