Role of the sympathetic nervous system in regulation of the sodium glucose cotransporter 2. Issue 10 (October 2017)

• Record Type: Journal Article
• Authors: Matthews, Vance B.; Elliot, Rosemary H.; Rudnicka, Caroline; Hricova, Jana; Herat, Lakshini; Schlaich, Markus P.
• Is Part Of: Journal of hypertension. Volume 35:Issue 10(2017:Oct.)
• Publication Date: 2017-10
• Subjects: heart -- high-fat diet -- kidney -- noradrenaline -- SGLT2 -- sympathetic -- tyrosine hydroxylase; Hypertension -- Periodicals; Hypertension -- Periodicals; 616.132005
• DOI: 10.1097/HJH.0000000000001434
• Languages: English
• ISSNs: 1473-5598

Abstract

Abstract : Background: The sympathetic nervous system (SNS) regulates glucose metabolism in various organs including the kidneys. The sodium glucose cotransporter 2 (SGLT2) mediates glucose reabsorption in renal proximal tubules and its inhibition has been shown to improve glucose control, cardiovascular and renal outcomes. We hypothesized that SNS-induced alterations of glucose metabolism may be mediated via regulation of SGLT2. Method: We used human renal proximal tubule cells to investigate the effects of noradrenaline on SGLT2 regulation. Mice fed a high-fat diet were oral gavaged with dapagliflozin and the expression of noradrenaline and tyrosine hydroxylase was measured in the kidney and heart. Results: Noradrenaline treatment resulted in a pronounced increase in SGLT2 and interleukin (IL)-6 expression in HK2 cells and promoted translocation of SGLT2 to the cell surface. In vivo, dapagliflozin treatment resulted in marked glucosuria in high-fat diet-fed mice. SGLT2 inhibition significantly reduced high-fat diet-induced elevations of tyrosine hydroxylase and noradrenaline in the kidney and heart. We also aimed to assess the levels of hypertension-related cytokines in the kidneys of our mice treated with and without dapagliflozin. Excitingly, we demonstrate that SGLT2 inhibition with dapagliflozin promoted a trend towards reduced tumour necrosis factor-alpha and elevated IL-1β protein levels in the kidney. Conclusion: Our in-vitro and in-vivo studies provide first evidence for an important cross-talk between the SNS and SGLT2 regulation that may not only account for SNS-induced alterations of glucose metabolism but potentially contribute to cardiovascular and renal protection observed with SGLT2 inhibitors. Abstract : Supplemental Digital Content is available in the text