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Aldosterone breakthrough caused by chronic blockage of angiotensin II type-1 receptors in human adrenocortical cells : Involvement of bone morphogenetic protein-6 actions

人肾上腺皮质细胞中血管紧张素 II 1 型受体慢性阻断引起的醛固酮突破：骨形态发生蛋白 6 作用的参与

基本信息

批准号：
21790894
负责人：
SUZUKI Jirou
金额：
$ 2.08万
依托单位：
Okayama University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Young Scientists (B)
财政年份：
2009
资助国家：
日本
起止时间：
2009 至 2010
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-21790894/
关键词：
アルドステロン骨形成蛋白シグナル伝達ステロイド合成

项目摘要

We investigated whether aldosterone breakthrough occurs in human adrenocortical H295R cells in vitro. We recently reported that bone morphogenetic protein (BMP)-6 enhances Ang II-induced aldosterone production in human adrenocortical cells. Ang II stimulation was blocked by an ARB, candesartan. Interestingly, the candesartan effects on Ang II-induced aldosterone synthesis was attenuated in a course of candesartan treatment for 15 d. The impairment of candesartan effects on Ang II-induced aldosterone production was also observed in Ang II- or candesartanpretreated cells. BMP-6 enhancement of Ang II-induced ERK1/2 signaling was resistant to candesartan. The BMP-6-induced Smad1, -5, and -8 phosphorylation was augmented in the presence of Ang II and candesartan in the chronic phase. Chronic Ang II exposure decreased cellular expression levels of BMP-6 and its receptors mRNAs. Cotreatment with candesartan reversed the inhibitory effects of Ang II on the expression levels of these mRNAs. The breakthrough phenomenon was attenuated by neutralization of endogenous BMP-6 and activin receptor-like kinase-2. Collectively, these data suggest that changes in BMP-6 availability and response may be involved in the occurrence of cellular escape from aldosterone suppression under chronic treatment with ARB.

我们研究是否醛固酮突破发生在人肾上腺皮质H295 R细胞在体外。我们最近报道，骨形态发生蛋白（BMP）-6增强血管紧张素II诱导的人肾上腺皮质细胞醛固酮的产生。血管紧张素II刺激被阻断的ARB，坎地沙坦。有趣的是，坎地沙坦对Ang II诱导的醛固酮合成的影响在坎地沙坦治疗15 d的过程中减弱。坎地沙坦对血管紧张素II诱导的醛固酮产生的影响的损害也观察到在血管紧张素II或坎地沙坦预处理的细胞。BMP-6增强Ang II诱导的ERK 1/2信号传导对坎地沙坦具有抗性。BMP-6诱导的Smad 1、Smad 5和Smad 8磷酸化在慢性期Ang II和坎地沙坦存在下增强。慢性Ang II暴露降低了BMP-6及其受体mRNA的细胞表达水平。与坎地沙坦共处理逆转了Ang II对这些mRNA表达水平的抑制作用。通过中和内源性BMP-6和激活素受体样激酶-2减弱突破现象。总的来说，这些数据表明，BMP-6的可用性和反应的变化可能参与ARB长期治疗下醛固酮抑制的细胞逃逸的发生。