ROLE OF ALDOSTERONE AND P66SHC PROTEIN ON EXPRESSION OF THE SODIUM-GLUCOSE TRANSPORTER SGLT2 IN THE VASCULAR SYSTEM

Abstract

Objective: SGLT2 is a transporter involved in sodium and glucose reabsorption in the kidney. SGLT2 inhibitors are a novel class of antidiabetic drugs which inhibit sodium and glucose reabsorption in the tubule, and they have shown a significant protective effect on cardiovascular outcomes in clinical trials. However the role of SGLT2 in the cardiovascular system is not fully elucidated. The aim of this study was to investigate the modulation of SGLT2 expression in the vascular system and kidney in a mouse model of aldosterone-induced hypertension and to explore the role of p66shc, through which aldosterone/MR signals. Design and method: Wild type mice (WT) and p66shc mice -/- (14 weeks, 6 per group) were treated or not with aldosterone (300 μg/kg/day) for 4 weeks. Systolic blood pressure (SBP) was measured by the tail-cuff method. The expression of SGLT2 and the mineralocorticoid receptor (MR) in the kidney and aorta was evaluated by immuno-blotting. Results: At the beginning of study SBP was similar in WT and p66shc-/-. Aldosterone increased SBP in both WT (192.3 ± 4.522 vs 103.3 ± 2.996; p < 0.05) and p66shc-/- mice (176.8 ± 5.313 vs 105.3 ± 1.542; p < 0.05), although at significant less extent in p66shc-/-. SGLT2 expression was significantly lower in p66shc -/- compared to WT in both kidney and aorta (-50%, for both tissues, p < 0.05). Aldosterone increased SGLT2 expression by 3-fold only in WT (p < 0.05) in aorta but not in the kidney. MR expression was similar in all groups. Conclusions: SGLT2 is expressed in vascular tissue as well as in the kidney. Aldosterone modulates its expression only in the vascular tissue, suggesting a tissue specific effect. The p66shc protein may be involved in the modulation of SGLT2 expression in both tissues. These findings suggest that aldosterone and p66shc adaptor protein may contribute to the modulation of SGLT2 expression in the vascular system. Thus SGLT2 may play a role in the vascular homeostatic functions of aldosterone-induced hypertension.