S-18-3: SGLT2 INHIBITOR CANAGLIFLOZIN ANTAGONIZES SALT-SENSITIVE HYPERTENSION THROUGH MODIFYING TRPC3 MEDIATED VASCULAR CALCIUM HANDLING

Abstract

Objectiv: Salt-sensitive hypertension is highly prevalent and associated with cardiorenal damage. Large clinical trials have demonstrated that Sodium-glucose cotransporter 2 (SGLT2) inhibitors exert hypotensive effect and cardiorenal protective benefits in hypertensive patients with and without diabetes. However, the underlying mechanism remains elusive. Methods: Dahl salt-sensitive (SS) rats and salt-insensitive controls were fed with 8% high salt diet to establish salt-sensitive hypertensive model, some of them were treated with canagliflozin. The blood pressure, urinary sodium excretion, vascular function and remodeling were detected. Rat aortic proteomics and TRPC3 knockout mice were used to explain the mechanism of the effect of canagliflozin on salt-sensitive hypertension. Results: Canagliflozin treatment significantly reduced high salt induced hypertension and this effect was not totally dependent on urinary sodium excretion in SS hypertensive rats. Assay of vascular function and proteomics showed that canagliflozin significantly inhibited vascular cytoplasmic calcium increase and vasoconstriction in response to high salt diet. High salt intake increased vascular expression of TRPC3 in salt-sensitive rats, which could be alleviated by canagliflozin treatment. Overexpression of TRPC3 mimicked salt-induced vascular cytosolic calcium increase in vitro and knockout of TRPC3 erased the anti-hypertensive effect of canagliflozin. Mechanistically, high-salt-induced activation of sodium/calcium exchanger 1 (NCX1) reverse mode increased cytoplasmic calcium level and vasoconstriction, which required TRPC3, and this process could be blocked by canagliflozin. Conclusions: We define a previously unrecognized role of TRPC3/NCX1 mediated vascular calcium dysfunction in the development of high salt induced hypertension, which can be improved by canagliflozin treatment. This pathway is potentially a novel therapeutic target to antagonize salt sensitive hypertension.