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Canagliflozin Reduces Proteinuria and Mitochondrial Fission in Membranous Nephropathy Rats via CAV1/PKA/DRP1
Xin Lv1, Liling Cui2, Hongyan Liu3
1Department of Nephrology, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Tongji Shanxi Hospital, Taiyuan, China, jzlxmm@163.com.
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.
Insights
Sodium-glucose cotransporter 2 inhibitors (SGLT2is) show promise for membranous nephropathy (MN). Canagliflozin reduces kidney damage by inhibiting mitochondrial fission and apoptosis via the CAV1/PKA/DRP1 pathway.
Area of Science:
- Nephrology
- Molecular Biology
- Pharmacology
Background:
- Sodium-glucose cotransporter 2 inhibitors (SGLT2is) offer renoprotection in chronic kidney disease (CKD).
- The role of SGLT2is in membranous nephropathy (MN) is not well-defined.
- Caveolin-1 (CAV1) is upregulated in MN, suggesting its involvement in disease progression.
Purpose of the Study:
- To investigate the therapeutic potential of canagliflozin in a rat model of membranous nephropathy.
- To explore the underlying mechanisms of canagliflozin's renoprotective effects, focusing on mitochondrial function and apoptosis.
- To examine the involvement of the CAV1/PKA/DRP1 signaling pathway.
Main Methods:
- Induced a rat model of MN using cationic bovine serum albumin (C-BSA).
- Treated rats with canagliflozin and assessed renal function and histology.
- Utilized in vitro podocyte models to investigate mitochondrial fission, apoptosis, and signaling pathways.
Main Results:
- Canagliflozin treatment significantly reduced proteinuria, improved serum albumin, and ameliorated renal histopathology in MN rats.
- Canagliflozin restored podocyte markers (nephrin, podocin) and inhibited the CAV1/PKA/DRP1 pathway.
- The drug preserved mitochondrial membrane potential, reduced Bax and cleaved caspase-3, and increased Bcl-2 expression.
Conclusions:
- Canagliflozin demonstrates renoprotective effects in membranous nephropathy.
- These benefits are mediated by the suppression of mitochondrial fission and apoptosis.
- Inhibition of the CAV1/PKA/DRP1 signaling axis is a key mechanism underlying canagliflozin's efficacy in MN.
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