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SIRT3 Activation by SGLT2 Inhibitor Mitigates Endothelial-To-Mesenchymal Transition in Dahl Salt-Sensitive Rats
Xiu-Heng Wang1, Jia-Yang Yang2, Zheng-Wen Lei3
1The First Affiliated Hospital,Department of Metabolism and Endocrinology, Hengyang Medical School, University of South China, Hengyang, Hunan, P.R. China.
American Journal of Hypertension
|October 28, 2025
Summary
Dapagliflozin (DAPA) treatment in salt-sensitive hypertension (SSHT) rats reduced myocardial fibrosis and atrial fibrillation by upregulating SIRT3 expression and mitigating endothelial-mesenchymal transition (EndMT). This highlights a key mechanism for SGLT2 inhibitors
Area of Science:
- Cardiovascular Research
- Metabolic Disease Research
- Pharmacology
Background:
- Salt-sensitive hypertension (SSHT) is linked to reduced SIRT3 expression and endothelial-mesenchymal transition (EndMT).
- Sodium-glucose cotransporter 2 (SGLT2) inhibitors, like dapagliflozin (DAPA), show promise in managing hypertension.
- The study investigates DAPA's potential to counteract SSHT-induced EndMT and fibrosis via SIRT3 modulation.
Purpose of the Study:
- To determine if DAPA attenuates SSHT-induced EndMT and myocardial fibrosis.
- To investigate the role of SIRT3 upregulation in DAPA's cardioprotective effects.
- To elucidate the mechanisms behind SGLT2 inhibitors' benefits in hypertension.
Main Methods:
- Dahl salt-sensitive rats were assigned to high-salt diet (HSD), normal-salt diet (NSD), or HSD with DAPA.
- Systolic blood pressure (SBP) was monitored.
- Left atrial tissues were analyzed for fibrosis and expression of SIRT3 and EndMT markers (CD31, Snail, FSP1, Twist, VE-cadherin, α-SMA).
Main Results:
- HSD rats showed increased SBP, atrial fibrosis, and EndMT markers (α-SMA, Snail, FSP1, Twist).
- HSD rats exhibited decreased SIRT3, CD31, and VE-cadherin expression, alongside impaired atrial function.
- DAPA treatment reversed these detrimental effects induced by the high-salt diet.
Conclusions:
- High-salt diet decreases SIRT3, promotes EndMT, and causes fibrosis in SSHT rats.
- DAPA mitigates high-salt-induced EndMT and fibrosis-related atrial fibrillation by upregulating SIRT3.
- This suggests SIRT3 upregulation is a key mechanism for SGLT2 inhibitors' cardioprotective action in SSHT.
