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 longterm 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 saltsensitive 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. Conflict of interest:The authors have declared that no conflict of interest exists. Nonstandard abbreviations used: arterial blood pressure (BP); angiotensinogen (AGT); renin-angiotensin system (RAS); transgenic (Tg); 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1); adipocyte fatty acid binding protein (aP2); heart rate (HR); mean arterial pressure (MAP); angiotensin II receptor AT-1 (AT-1 receptor); radioimmunoassay (RIA).

Glucocorticoid synthesis-related genes:HSD11B1andHSD11B2in hypertensive disorders in pregnancy

“…On the other hand, transgenic mice that overexpress 11b-HSD1 have been found to have an increased sensitivity to dietary salt and exhibit increased plasma levels of angiotensinogen, angiotensin II and aldosterone. Moreover, these mice showed histological changes of the kidney that included distal tubular hypertrophy and hyperplasia that started immediately proximal to the macula densa [28]. Therefore, based on the assumption that 11b-HSD1 is critical for the establishment and maintenance of the glomerular filtration barrier, it is reasonable to expect that HSD11B1 polymorphisms would affect the development of PE, but not GH, similar to the results that were found in our present study.…”

Upregulation of Hepatic 11β-Hydroxysteroid Dehydrogenase-1 Expression in Calcium-Deficient Rats

“…Overactivity of 11β-HSD1 is associated with increased intracellular active glucocorticoids. Genetic studies in rodents suggest that increased 11β-HSD1 expression or activity increases the risk of several components of metabolic syndrome [12,13]. However, the role of 11β-HSD1 in cortisol metabolism seems to be complex.…”

“…11β-HSD1 is highly expressed in the liver and adipose tissue where glucocorticoids reduce insulin sensitivity and action [9,10,11]. Activity of 11β-HSD1 in the liver and adipose tissue might contribute to the development of several features of insulin resistance or metabolic syndrome [12,13]. 11β-HSD2 converts excess cortisol to inactive cortisone [14].…”

Metabolic Syndrome in Cushing’s Syndrome

“…11βHSD1 is expressed in liver, adipose tissue, bone and the central nervous system. Mice with 11βHSD1 overexpression or over-activity develop several features of MetS [26], while 11βHSD1 knockout mice have a reduced risk of obesity and MetS [27,28]. Human data on the relationship between 11βHSD1 expression and parameters of visceral adipose tissue or liver are much more controversial [29].…”