Insulin mediated upregulation of the renin angiotensin system in human subcutaneous adipocytes is reduced by Rosiglitazone
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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Official URL: http://dx.doi.org/10.1161/01.CIR.0000161954.17870....
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|
|Page Range:||pp. 1654-1961|
|Access rights to Published version:||Open Access|
Version accepted by publisher (post-print, after peer review, before copy-editing).
1. Must A, Spandano J, Coakley EH, Field AE, Colditz G, Dietz WH. The disease burden associated with overweight and obesity. JAMA 1999; 282: 1523-9.
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