Transgenic amplification of glucocorticoid action in adipose tissue causes high blood pressure in mice
Hiroaki Masuzaki, … , Jonathan R. Seckl, Jeffrey S. Flier
Hiroaki Masuzaki, … , Jonathan R. Seckl, Jeffrey S. Flier
Published July 1, 2003
Citation Information: J Clin Invest. 2003;112(1):83-90. https://doi.org/10.1172/JCI17845.
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Article Endocrinology

Transgenic amplification of glucocorticoid action in adipose tissue causes high blood pressure in mice

Abstract

Obesity is closely associated with the metabolic syndrome, a combination of disorders including insulin resistance, diabetes, dyslipidemia, and hypertension. A role for local glucocorticoid reamplification in obesity and the metabolic syndrome has been suggested. The enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) regenerates active cortisol from inactive 11-keto forms, and aP2-HSD1 mice with relative transgenic overexpression of this enzyme in fat cells develop visceral obesity with insulin resistance and dyslipidemia. Here we report that aP2-HSD1 mice also have high arterial blood pressure (BP). The mice have increased sensitivity to dietary salt and increased plasma levels of angiotensinogen, angiotensin II, and aldosterone. This hypertension is abolished by selective angiotensin II receptor AT-1 antagonist at a low dose that does not affect BP in non-Tg littermates. These findings suggest that activation of the circulating renin-angiotensin system (RAS) develops in aP2-HSD1 mice. The long-term hypertension is further reflected by an appreciable hypertrophy and hyperplasia of the distal tubule epithelium of the nephron, resembling salt-sensitive or angiotensin II–mediated hypertension. Taken together, our findings suggest that overexpression of 11β-HSD1 in fat is sufficient to cause salt-sensitive hypertension mediated by an activated RAS. The potential role of adipose 11β-HSD1 in mediating critical features of the metabolic syndrome extends beyond obesity and metabolic complications to include the most central cardiovascular feature of this disorder.

Authors

Hiroaki Masuzaki, Hiroshi Yamamoto, Christopher J. Kenyon, Joel K. Elmquist, Nicholas M. Morton, Janice M. Paterson, Hiroshi Shinyama, Matthew G.F. Sharp, Stewart Fleming, John J. Mullins, Jonathan R. Seckl, Jeffrey S. Flier

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Figure 2

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(a) Effect of high-salt diet on MAP in aP2-HSD1 mice. The aP2-HSD1 mice ...
(a) Effect of high-salt diet on MAP in aP2-HSD1 mice. The aP2-HSD1 mice and non-Tg littermates at 19 weeks of age were given a high-salt (8%) diet for 3 weeks. The graph on the left shows that MAP in non-Tg mice (n = 4) fed a high-salt diet (filled circles) did not elevate significantly compared with the initial values when fed a chow diet with 1% salt (open circles). The graph at right shows that MAP in Tg mice fed a high-salt diet (filled squares) (n = 5) was significantly elevated during most of the day (except 0700 hours to 0800 hours, 1500 hours to 1600 hours, and 1800 hours to 2400 hours), by 10–20 mmHg compared with Tg mice fed a normal diet (open squares). *P < 0.05 vs. Tg mice fed a chow diet. (b) Effect of the specific AT-1 receptor antagonist GA0113 on MAP in aP2-HSD1 mice fed a high-salt diet. Four days of low-dose administration of GA0113 (0.1 mg/kg body weight, which does not lower MAP in non-Tg mice) to Tg mice fed a high-salt diet (22 weeks of age, n = 4) (open squares) markedly abrogated MAP elevation to approximately that of non-Tg mice (filled squares) fed chow diet. *P < 0.05 vs. Tg mice fed a high-salt diet.