SIRT3 Activation by SGLT2 Inhibitor Mitigates Endothelial-To-Mesenchymal Transition in Dahl Salt-Sensitive Rats Induced by High-Salt Diet

Abstract

Background: Salt-sensitive hypertension (SSHT) is associated with reduced expression of SIRT3 and promotes endothelial-mesenchymal transition (EndMT). Sodium-glucose cotransporter 2 (SGLT2) inhibitors, such as dapagliflozin (DAPA), have been shown to ameliorate high-salt-induced hypertension. We hypothesized that DAPA attenuate SSHT-induced EndMT and reduce myocardial fibrosis by upregulating SIRT3 expression. This study aims to provide new insights into the mechanisms underlying the cardioprotective effects of SGLT2 inhibitors in hypertension.

Methods: Seven-week-old male Dahl salt-sensitive rats were fed either a high-salt diet (8% NaCl; HSD group), a normal-salt diet (0.3% NaCl; NSD group), or an HSD supplemented with DAPA (2 mg/kg/day administered via drinking water). Systolic blood pressure (SBP) was measured, and left atrial tissue was examined for fibrosis and the expression of SIRT3 and EndMT-related markers, including CD31, Snail, FSP1, Twist, VE-cadherin, and α-SMA.

Results: Compared with the NSD group, the HSD group exhibited increased SBP, left atrial end-systolic volume index (LAESVI), incidence and duration of atrial fibrillation (AF), and atrial fibrosis. Expression of α-SMA, Snail, FSP1, and Twist was elevated, while SIRT3, CD31, and VE-cadherin expression were decreased, along with reduced left atrial ejection fraction and left atrial function index. DAPA treatment reversed these changes.

Conclusions: Our findings indicate that a high-salt diet decreases SIRT3 expression, induces EndMT, and promotes myocardial fibrosis in SSHT rats. DAPA mitigates high-salt-induced EndMT and fibrosis-related AF by upregulating SIRT3, suggesting a potential mechanism for the cardioprotective effects of SGLT2 inhibitors in SSHT.

Keywords: Sodium-glucose cotransporter 2 inhibitors; atrial fibrosis; blood pressure; endothelial mesenchymal transition; salt-sensitive hypertension.