Background: Sympathetic nervous system (SNS) activation is a common feature in obesity and type-2 diabetes and regulates glucose metabolism in organs including the kidneys. The sodium glucose co-transporter 2 (SGLT-2) mediates re-absorption of glucose from the renal proximal tubules in the kidney. SGLT-2 inhibitors have garnered attention due to their glucose lowering effects and associated improvement in both cardiovascular and renal outcomes. We hypothesized that SGLT-2 inhibitor-induced alterations of SNS activation may contribute to these favorable effects.
Aims: Firstly, to investigate the hypothesis that SGLT-2 is up-regulated by norepinephrine (NE), the main neurotransmitter of the SNS. Secondly, to determine whether SGLT-2 inhibition may reduce SNS activity in vivo. Thirdly, to assess whether the SGLT-2 inhibitor induced blood pressure reduction is mediated by alterations in SNS activity in vivo.
Methods: Human renal proximal tubule cells (HK2) were treated with NE and SGLT-2 expression was determined. We determined the influence of SGLT-2 inhibition with dapagliflozin (DAPA) on blood pressure levels in normotensive and hypertensive mice and also the SNS activity in vivo. Expression of NE and the sympathetic nerve protein tyrosine hydroxylase was measured in the kidney and heart.
Results: A marked increase in SGLT-2 and IL-6 expression in HK2 cells and translocation of SGLT2 to the cell surface could be demonstrated in response to NE treatment. In vivo, DAPA treatment resulted in marked glucosuria in high fat diet fed mice. Importantly, SGLT-2 inhibition in vivo significantly reduced blood pressure and this was associated with reduced NE and tyrosine hydroxylase levels in the kidney and heart.
Conclusions: Our in vitro and in vivo studies provide first evidence for an important cross-talk between the SNS and SGLT-2 regulation, which may not only account for SNS-induced alterations of glucose metabolism but may potentially contribute to cardiovascular and renal protection observed with SGLT2 inhibitors.