Sodium-glucose cotransporter 2 inhibitors (SGLT2is) have demonstrated renoprotective effects in chronic kidney disease (CKD), but their therapeutic potential in membranous nephropathy (MN) remains unclear. In this study, analysis of the GEO database revealed that CAV1 expression is significantly upregulated in MN, suggesting a potential role in disease progression. A rat MN model was induced with cationic bovine serum albumin (C-BSA) and treated with canagliflozin (10 mg/kg). Renal function and histopathological changes were assessed. In vitro, MPC-5 podocytes were injured with complement C5a and treated with canagliflozin or CAV1 overexpression to explore mechanisms related to mitochondrial fission and apoptosis. Canagliflozin treatment markedly reduced proteinuria, increased serum albumin, and improved renal histology, including attenuation of mesangial hyperplasia, basement membrane thickening, and subepithelial electron-dense deposits. It also restored the expression of podocyte markers nephrin and podocin, inhibited the CAV1/PKA/DRP1 signaling pathway, preserved mitochondrial membrane potential, reduced pro-apoptotic markers Bax and cleaved caspase-3, and upregulated the anti-apoptotic protein Bcl-2. These findings suggest that canagliflozin alleviates podocyte injury and renal damage in MN by suppressing mitochondrial fission and apoptosis through inhibition of the CAV1/PKA/DRP1 signaling axis.
Lv et al. (Fri,) studied this question.