Interaction between SGLT2 and the sympathetic nervous system in normal and various cardiovascular metabolic disease states.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been shown to suppress cardiovascular events and are widely used for treating diabetes, chronic heart failure and chronic kidney disease. Although the underlying mechanisms by which SGLT2 inhibitors suppress cardiovascular events are not entirely clear, several mechanisms have been proposed to explain the cardiorenal protective effects of SGLT2 inhibitors. One of these involves sympathoinhibition. In vitro, SGLT2 expression is upregulated by norepinephrine, and SGLT2 inhibitors have been shown to attenuate SGLT2 expression and normalize the diuretic response to volume expansion with isotonic saline in rats with heart failure. These findings suggest that inhibition of renal sympathetic nerve activity is the mechanism underlying the beneficial effects of SGLT2 inhibitors on heart failure. Increased resting afferent renal nerve activity has been observed in several disease models, including models of hypertension, heart failure, and kidney disease, and might induce augmented sympathetic outflow via the central nervous system. SGLT2 inhibitors may suppress afferent renal nerve activity via intrarenal environmental modifications such as renal tissue hypoxia, inflammation, oxidative stress, mitochondrial function, and congestion, thereby inhibiting sympathetic outflow to the peripheral organs, including the heart and kidneys. On the other hand, SGLT2 is also expressed in the brain, and electrophysiological techniques in rats have shown that SGLT2 inhibitors suppress the activities of the rostral ventrolateral medulla neurons which project to the sympathetic preganglionic nuclei of the spinal cord to control sympathetic outflow, suggesting decreased sympathetic nerve activities. This mini review focuses on the bidirectional interaction between SGLT2 and the sympathetic nervous system and introduces recent related findings from Hypertension Research and other journals.