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Insulin mediated upregulation of the renin angiotensin system in human subcutaneous adipocytes is reduced by Rosiglitazone

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Harte, A. L. (Alison L.), McTernan, P. G. (Philip G.), Chetty, Rajkumar, Coppack, Simon, Katz, Jonathan, Smith, Stephen and Kumar, Sudhesh. (2005) Insulin mediated upregulation of the renin angiotensin system in human subcutaneous adipocytes is reduced by Rosiglitazone. Circulation, Vol.111 . pp. 1654-1961. ISSN 0009-7322

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Abstract

Background: Obesity associated hypertension is likely to be due to multiple mechanisms. Identification of the renin-angiotensin system (RAS) within adipose tissue does, however, suggest a potential causal role for it in obesity-associated hypertension. Obese patients are often hyperinsulinaemic, but mechanisms underlying insulin upregulation of the RAS in adipose tissue are unclear. TNFα, an inducer of angiotensinogen in hepatocytes, is elevated in hyperinsulinaemic, obese individuals, and may provide a link in mediating insulin upregulation of the RAS in adipose tissue. Further, thiazolidinediones lower blood pressure in vivo and downregulation of the RAS in adipose tissue may contribute to this effect. We therefore examined the effect of rosiglitazone (RSG), on the insulin mediated upregulation of the RAS.
Methods and Results: Sera were obtained from the arterial circulation and from venous blood draining subcutaneous abdominal adipose tissue. Isolated human abdominal subcutaneous adipocytes (n=12) were treated with insulin (1-1000nM) and insulin in combination with RSG (10nM), and RSG (10nM) alone to determine angiotensinogen expression, angiotensin II, bradykinin and TNFα secretion. Subcutaneous adipocytes were also treated with TNFα (10-100ng/mL) to examine the direct effect on angiotensinogen expression and angiotensin II secretion. The findings showed that the arterio-venous difference in angiotensin II levels was significant (↑23%; p<0.001). Insulin increased TNFα secretion in a concentration-dependent manner (p<0.01) whilst RSG (10nM) significantly reduced the insulin mediated rise in TNFα (p<0.001), as well as AGT and angiotensin II. TNFα also increased angiotensinogen and angiotensin II in isolated adipocytes.
Conclusions: Our in vivo data suggest that human subcutaneous adipose tissue is a significant source of angiotensin II. This study also demonstrates a potential TNFα mediated
mechanism through which insulin may stimulate the RAS and may contribute to explain obesity associated hypertension. RSG downregulates the RAS in subcutaneous adipose tissue and this effect may contribute to the long-term effect of RSG on blood pressure.

Item Type: Journal Article
Subjects: R Medicine > RC Internal medicine
Divisions: Faculty of Medicine > Warwick Medical School
Library of Congress Subject Headings (LCSH): Obesity, Hypertension, Angiotensin II, Adipose tissues
Journal or Publication Title: Circulation
Publisher: American Heart Association
ISSN: 0009-7322
Official Date: 2005
Volume: Vol.111
Page Range: pp. 1654-1961
Identification Number: 10.1161/01.CIR.0000161954.17870.5D
Status: Peer Reviewed
Access rights to Published version: Open Access
Description:

Version accepted by publisher (post-print, after peer review, before copy-editing).
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URI: http://wrap.warwick.ac.uk/id/eprint/167

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