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Canagliflozin Reduces Proteinuria and Mitochondrial Fission in Membranous Nephropathy Rats via CAV1/PKA/DRP1 Inhibition
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DOI：10.1159/000550928.png)
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Abstract
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Introduction: Membranous nephropathy (MN) is a common glomerular disease characterized by immune complex deposition, glomerular filtration barrier impairment, and severe proteinuria, which may potentially progress to end-stage kidney disease. Podocyte injury and mitochondrial dysfunction are key pathological features of MN. Caveolin-1 (CAV1) is upregulated in MN, and we hypothesized canagliflozin alleviates MN via inhibiting the CAV1/PKA/DRP1 pathway. Methods: The publicly available GEO dataset GSE115857 was analyzed for CAV1 expression. MN rats induced by cationic bovine serum albumin were treated with canagliflozin (10 mg/kg/day). MPC-5 podocytes were stimulated with C5a and treated with canagliflozin or CAV1 overexpression. Renal function, histopathology, apoptosis, mitochondrial membrane potential (MMP), and pathway-related proteins were assessed. Results: The results of this study show that CAV1 was upregulated in MN. Canagliflozin reduced proteinuria, increased serum albumin, and improved renal histology in MN rats. It restored podocyte markers (nephrin and podocin), inhibited CAV1/PKA/DRP1 signaling, preserved MMP, suppressed proapoptotic proteins (Bax and caspase-3), and upregulated Bcl-2. CAV1 overexpression reversed canagliflozin's protective effects. Conclusion: Our study demonstrates that canagliflozin alleviates MN by inhibiting the CAV1/PKA/DRP1 pathway, suppressing mitochondrial fission and podocyte apoptosis, and supporting its potential clinical application in MN.
Keywords:
Canagliflozin
Membranous nephropathy
Mitochondrial fission
CAV1
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