Role of the sympathetic nervous system in regulation of the sodium glucose cotransporter 2

Vance B. Matthews, Rosemary H. Elliot, Caroline Rudnicka, Jana Hricova, Lakshini Herat, Markus P. Schlaich

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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.

Original languageEnglish
Pages (from-to)2059–2068
JournalJournal of Hypertension
Volume35
Issue number10
DOIs
Publication statusPublished - 1 Oct 2017

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Sodium-Glucose Transport Proteins
Sympathetic Nervous System
Kidney
Norepinephrine
High Fat Diet
Glucose
Proximal Kidney Tubule
Tyrosine 3-Monooxygenase
Interleukin-1
Interleukin-6
Tumor Necrosis Factor-alpha

Cite this

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title = "Role of the sympathetic nervous system in regulation of the sodium glucose cotransporter 2",
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.",
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Role of the sympathetic nervous system in regulation of the sodium glucose cotransporter 2. / Matthews, Vance B.; Elliot, Rosemary H.; Rudnicka, Caroline; Hricova, Jana; Herat, Lakshini; Schlaich, Markus P.

In: Journal of Hypertension, Vol. 35, No. 10, 01.10.2017, p. 2059–2068.

Research output: Contribution to journalArticle

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T1 - Role of the sympathetic nervous system in regulation of the sodium glucose cotransporter 2

AU - Matthews, Vance B.

AU - Elliot, Rosemary H.

AU - Rudnicka, Caroline

AU - Hricova, Jana

AU - Herat, Lakshini

AU - Schlaich, Markus P.

PY - 2017/10/1

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