Glucocorticoid receptor haploinsufficiency causes hypertension and attenuates hypothalamic-pituitary-adrenal axis and blood pressure adaptions to high-fat diet
Glucocorticoid receptor haploinsufficiency causes hypertension and attenuates hypothalamic-pituitary-adrenal axis and blood pressure adaptions to high-fat diet
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DOI：
10.1096/fj.08-111914
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发表时间：
2008-11-01
期刊：
影响因子：
4.8
通讯作者：
Chapman, K. E.
中科院分区：
文献类型：
--
作者：
Michailidou, Z.;Carter, R. N.;Chapman, K. E.
糖皮质激素对应对和适应压力至关重要。糖皮质激素受体（GR）基因的遗传变异改变了下丘脑-垂体-肾上腺（HPA）轴的活性，并与高血压和代谢性疾病的易感性有关。在这里，我们测试的假设，减少GR密度改变血压和血糖和脂质的稳态和限制适应肥胖饮食。从胚胎干（ES）细胞中产生杂合子GR（β geo/+）小鼠，其中基因陷阱将β-半乳糖苷酶-新霉素磷酸转移酶（β geo）盒整合到GR基因中，产生转录失活的GR融合蛋白。尽管GR（beta geo/+）小鼠具有50%的功能性GR，但是由于代偿性HPA轴激活，它们具有正常的脂质和葡萄糖稳态，但是由于肾素-血管紧张素-醛固酮系统（RAAS）的激活，它们是高血压的。当用高脂饮食挑战时，对照和GR（beta geo/+）小鼠中的体重增加、肥胖和葡萄糖耐受不良类似地增加，这表明保留了对中间代谢和能量平衡的控制。然而，尽管高脂饮食导致对照小鼠HPA激活和血压升高，但这些适应在GR（beta geo/+）小鼠中减弱或消除。因此，减少GR密度平衡HPA激活叶糖皮质激素的功能不受影响，但盐皮质激素的功能增加，导致高血压。重要的是，降低GR限制了HPA和血压对致肥胖饮食的适应。- Michailidou，Z.，卡特河，巴西-地N.，马歇尔，萨瑟兰，H。G.，Brownstein，D. G.，欧文，E.，Cockett，K.，凯利，V，拉梅奇湖Al-Dujaili，E. a.美国，罗斯，M.，马拉基岛牛顿，K.，霍姆斯，M。C.的方法，Seckl，J.R.，莫顿，N。M.，凯尼恩角J.，Chapman，K. e.糖皮质激素受体单倍不足引起高血压，并减弱下丘脑-垂体-肾上腺轴和血压对高脂饮食的适应。FASEB J. 22，3896 - 3907（2008）
Glucocorticoid hormones are critical to respond and adapt to stress. Genetic variations in the glucocorticoid receptor (GR) gene alter hypothalamic-pituitary-adrenal (HPA) axis activity and associate with hypertension and susceptibility to metabolic disease. Here we test the hypothesis that reduced GR density alters blood pressure and glucose and lipid homeostasis and limits adaption to obesogenic diet. Heterozygous GR(beta geo/+) mice were generated from embryonic stem (ES) cells with a gene trap integration of a beta-galactosidase-neomycin phosphotransferase (beta geo) cassette into the GR gene creating a transcriptionally inactive GR fusion protein. Although GR(beta geo/+) mice have 50% less functional GR, they have normal lipid and glucose homeostasis due to compensatory HPA axis activation but are hypertensive due to activation of the renin-angiotensin-aldosterone system (RAAS). When challenged with a high-fat diet, weight gain, adiposity, and glucose intolerance were similarly increased in control and GR(beta geo/+) mice, suggesting preserved control of intermediary metabolism and energy balance. However, whereas a high-fat diet caused HPA activation and increased blood pressure in control mice, these adaptions were attenuated or abolished in GR(beta geo/+) mice. Thus, reduced GR density balanced by HPA activation leaves glucocorticoid functions unaffected but mineralocorticoid functions increased, causing hypertension. Importantly, reduced GR limits HPA and blood pressure adaptions to obesogenic diet. -Michailidou, Z., Carter, R. N., Marshall, E., Sutherland, H. G., Brownstein, D. G., Owen, E., Cockett, K., Kelly, V., Ramage, L., Al-Dujaili, E. A. S., Ross, M., Maraki, I., Newton, K., Holmes, M. C., Seckl, J. R., Morton, N. M., Kenyon, C. J., Chapman, K. E. Glucocorticoid receptor haploinsufficiency causes hypertension and attenuates hypothalamic-pituitary-adrenal axis and blood pressure adaptions to high-fat diet. FASEB J. 22, 3896-3907 (2008)