Canagliflozin improves high-salt-induced aortic arteriosclerosis and premature aging in dahl salt-sensitive rats through the SIRT6/HIF-1 α signaling pathway.

Abstract

Hypertension and its complications seriously affect human health, bringing about long-term medical burdens, functional impairments and even death. This study explored the impact of Canagliflozin (CANA) on the blood vessels of salt-sensitive hypertension. Male Dahl salt-sensitive (Dahl SS) rats were fed with an 8% high-salt diet, and then intragastrically given CANA at a dose of 30 mg/kg/day or with a 0.5% hydroxypropyl methylcellulose solution for 12 weeks to induce hypertensive vascular damage and premature aging. Through vascular ultrasound detection, CANA improved the aortic stiffness and hemodynamics of high-salt-fed rats. Through vascular reactivity tests, CANA improved the carotid artery vasodilation. Hematoxylin and eosin (H&E), Sirius red, and senescence associated β-galactosidase staining were performed on the aorta, and CANA improved the fibrosis and aging of the aorta. CANA was found to reduce the expression of senescence associated secretory phenotype in the circulation that was induced by a high-salt diet. Additionally, it increased the expression of Sirtuin 6(SIRT6) in blood vessels and decreased the expression of Hypoxia-inducible factor 1α (HIF-1α) and its target genes. This study has demonstrated for the first time that CANA mitigates salt-induced aortic sclerosis and premature aging via the SIRT6/HIF-1α pathway.