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(Circulation. 2005;111:1954-1961.)
© 2005 American Heart Association, Inc.

Molecular Cardiology

Insulin-Mediated Upregulation of the Renin Angiotensin System in Human Subcutaneous Adipocytes Is Reduced by Rosiglitazone

Alison Harte, PhD^*; Philip McTernan, PhD^*; Rajkumar Chetty, MChB; Simon Coppack, MD; Jonathan Katz, MD; Stephen Smith, PhD; Sudhesh Kumar, MD

From the Unit for Diabetes and Metabolism (A.H., P.M., R.C., S.K.), Warwick Medical School, University of Warwick, Walsgrave, Coventry, United Kingdom; St. Bartholomew’s and The Royal London School of Medicine (S.C., J.K.), London, United Kingdom; and Glaxo-SmithKline (S.S.), Harlow, United Kingdom.

Correspondence to Professor S. Kumar, Unit for Diabetes and Metabolism, Warwick Medical School, University of Warwick, Coventry, CV4 7AL, United Kingdom. E-mail Sudhesh.Kumar{at}warwick.ac.uk

Received November 5, 2004; revision received February 4, 2005; accepted February 22, 2005.

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 hyperinsulinemic, but mechanisms underlying insulin upregulation of the RAS in adipose tissue are unclear. Tumor necrosis factor- (TNF-), an inducer of angiotensinogen in hepatocytes, is elevated in hyperinsulinemic, obese individuals and may provide a link in mediating insulin upregulation of the RAS in adipose tissue. Furthermore, 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 by draining subcutaneous abdominal adipose tissue. Isolated human abdominal subcutaneous adipocytes (n=12) were treated with insulin (1 to 1000 nmol/L), insulin in combination with RSG (10 nmol/L), and RSG (10 nmol/L) alone to determine angiotensinogen expression and angiotensin II, bradykinin, and TNF- secretion. Subcutaneous adipocytes were also treated with TNF- (10 to 100 ng/mL) to examine the direct effect on angiotensinogen expression and angiotensin II secretion. The findings showed that the arteriovenous difference in angiotensin II levels was significant (>23%; P<0.001). Insulin increased TNF- secretion in a concentration-dependent manner (P<0.01), whereas RSG (10 nmol/L) significantly reduced the insulin-mediated rise in TNF- (P<0.001), as well as angiotensin and angiotensin II. TNF- also increased angiotensinogen and angiotensin II in isolated adipocytes.

Conclusions— The present in vivo data suggest that human subcutaneous adipose tissue is a significant source of angiotensin II. This study also demonstrates a potential TNF-–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.

Key Words: obesity • hypertension • angiotensin

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