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Synthesis and action of mineralocorticoids in cardiovascular systems

盐皮质激素的合成及其在心血管系统中的作用

基本信息

批准号：
16570122
负责人：
MUKAI Kuniaki
金额：
$ 2.43万
依托单位：
Keio University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16570122/
关键词：
steroid hormone mineralocorticoid aldosterone glucocorticoid aldosterone synthase mineralocorticid receptor

项目摘要

Aldosterone is a most potent mineralocorticoid which regulates water and electrolyte metabolisms in mammals. This steroid hormone is synthesized and secreted from the zona glomerulosa of adrenal cortex, and acts through mineralocorticoid receptor (MR) in the epithelial cells transport water and electrolytes. Recently, however, evidence that aldosterone is synthesized in the cardiovascular systems and acts in a paracrine manner through MR has been reported. It has been known that aldosterone is involved in cardiac hypertrophy and fibrosis and in homeostasis of vasculature. In this study, we examined molecular basis for synthesis and action of aldosterone in the cardiovascular systems. Examination of mRNA level of aldosterone synthase in aortas and hearts of normal rats showed that it was detectable but almost at its detection limit. mRNAs of factors responsible for aldosterone action were easily detectable. Next, we employed Dahl salt-sensitive rats fed on 8% NaCl-containing diets as an … More animal model for aldosterone-inducible heart failure. Salt-loading resulted in induction of aldosterone synthase mRNA frequently, while expression levels of the factors for aldosterone action mostly did not changed. Interestingly, expression of a newly cloned factor AZ-1, whose expression correlates with aldosterone synthesis and action, was enhanced in aortas and hearts significantly. Furthermore, we used another experimental animal model of cardiac hypertrophy and fibrosis by continuous administration (6 weeks) of aldosterone into normal rats fed on 1% NaCl-containing drinking water. The aldosterone administration caused hypertension with systolic blood pressure at 170 mmHg. Judging from histochemical analysis of the hearts they showed hypertrophy with accumulating collagenous fibrils. Immunohistochemical examination with anti-AZ-1 antibody revealed that AZ-1 became detectable in capillaries and interstitial spaces between cardiac muscle cells. Aldosterone caused cardiac hypertrophy and fibrosis through MR and induced expression of extracellular matrix proteins including AZ-1. Less

醛固酮是一种调节哺乳动物水电解质代谢的强有力的盐皮质激素。这种类固醇激素由肾上腺皮质的肾小球合成和分泌，并通过上皮细胞中的盐皮质激素受体（MR）转运水和电解质发挥作用。然而，最近有证据表明，醛固酮是在心血管系统中合成的，并通过MR以旁分泌方式发挥作用。已知醛固酮参与心脏肥大和纤维化以及血管系统的稳态。在这项研究中，我们研究了醛固酮在心血管系统中的合成和作用的分子基础。对正常大鼠心脏和心脏醛固酮合成酶mRNA水平的检测表明，它是可检测的，但几乎在其检测限。负责醛固酮作用的因子的mRNA很容易检测。接下来，我们采用了Dahl盐敏感大鼠，喂食含8% NaCl的饮食， ...更多信息用于醛固酮诱导的心力衰竭的动物模型。盐负荷导致醛固酮合成酶mRNA的诱导频繁，而醛固酮作用因子的表达水平大多没有改变。有趣的是，新克隆的因子AZ-1的表达在主动脉和心脏中显着增强，该因子的表达与醛固酮的合成和作用相关。此外，我们使用了另一种心脏肥大和纤维化的实验动物模型，通过连续给药（6周）醛固酮到正常大鼠喂食含1%NaCl的饮用水。醛固酮给药引起高血压，收缩压为170 mmHg。从心脏的组织化学分析来看，它们显示出肥厚和胶原纤维积聚。用抗AZ-1抗体的免疫组织化学检查显示AZ-1在毛细血管和心肌细胞间质中变得可检测。醛固酮通过MR引起心肌肥厚和纤维化，并诱导细胞外基质蛋白（包括AZ-1）的表达。少