Are the Cardiorenal Benefits of SGLT2 Inhibitors Due to Inhibition of the Sympathetic Nervous System?∗

Visual Abstract
Highlights • SGLT2 inhibitors improve cardiovascular outcomes. • SGLT2 inhibitor–induced sympathetic nervous system inhibition may be an underlying mechanism. • Chemical denervation in neurogenic hypertensive mice reduces renal SGLT2 expression. • SGLT2 inhibition lowered blood pressure and resulted in significantly reduced tyrosine hydroxylase and norepinephrine levels in the kidney tissue of neurogenic hypertensive mice. • Crosstalk between the sympathetic nervous system and SGLT2 regulation appears as a key mechanism of the cardiorenal protective effects demonstrated with SGLT2 inhibition.
Summary Recent clinical trial data suggest a cardiorenal protective effect of sodium glucose cotransporter 2 (SGLT2) inhibition. We demonstrate that chemical denervation in neurogenic hypertensive Schlager (BPH/2J) mice reduced blood pressure, improved glucose homeostasis, and reduced renal SGLT2 protein expression. Inhibition of SGLT2 prevented weight gain, reduced blood pressure, significantly reduced elevations of tyrosine hydroxylase and norepinephrine, and protects against endothelial dysfunction. These findings provide evidence for significant crosstalk between activation of the sympathetic nervous system and SGLT2 regulation and possible ancillary effects on endothelial function, which may contribute to the observed cardiorenal protective effects of SGLT2 inhibition.