Transgenic amplification of glucocorticoid action in adipose tissue causes high blood pressure in mice
Transgenic amplification of glucocorticoid action in adipose tissue causes high blood pressure in mice
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DOI：
10.1172/jci200317845
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发表时间：
2003-07-01
影响因子：
15.9
通讯作者：
Flier, JS
中科院分区：
文献类型：
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作者：
Masuzaki, H;Yamamoto, H;Flier, JS
肥胖与代谢综合征密切相关，代谢综合征是一种包括胰岛素抵抗、糖尿病、血脂异常和高血压在内的多种疾病的组合。局部糖皮质激素再扩增在肥胖和代谢综合征中的作用已被提出。酶11β-羟基类固醇脱氢酶1(11β-HSD1)从非活性的11-酮形式再生活性皮质醇，在脂肪细胞中该酶相对转基因过表达的aP2-HSD1小鼠发生内脏肥胖并伴有胰岛素抵抗和血脂异常。在这里，我们报告aP2-HSD1小鼠也有高血压(BP)。小鼠对食盐的敏感性增加，血浆血管紧张素原、血管紧张素II和醛固酮水平增加。选择性血管紧张素11受体AT-1拮抗剂在不影响非TG产仔血压的小剂量下可消除这种高血压。这些发现表明，循环肾素-血管紧张素系统(RAS)的激活在aP2-HSD1小鼠中发生。长期高血压进一步表现为肾单位远端小管上皮细胞明显肥大和增生，类似于盐敏感型或血管紧张素II介导的高血压。综上所述，我们的研究结果表明，脂肪中11β-HSD1的过度表达足以导致RAS激活所介导的盐敏感性高血压。脂肪11β-HSD1在调节代谢综合征的关键特征方面的潜在作用不仅限于肥胖和代谢并发症，还包括这种疾病的最中心的心血管特征。
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 11 P-hydroxysteroid dehydrogenase type 1 (11 beta-HSD 1) 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 11 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 11beta-HSD1 in fat is sufficient to cause salt-sensitive hypertension mediated by an activated RAS. The potential role of adipose 11beta-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.