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

我们在体外研究了醛固酮是否在人肾上腺皮质H295R细胞中发生突破。我们最近报道了骨形态发生蛋白(BMP)-6增强Ang ii诱导的人肾上腺皮质细胞醛固酮的产生。Ang II刺激被ARB坎地沙坦阻断。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天后减弱。在Ang II或坎地沙坦预处理的细胞中也观察到坎地沙坦对Ang II诱导的醛固酮合成的影响受损。BMP-6增强的Ang ii诱导的ERK1/2信号对坎地沙坦具有耐药性。在慢性期，bmp -6诱导的Smad1、-5和-8磷酸化在Ang II和坎地沙坦的存在下增强。慢性angii暴露降低了BMP-6及其受体mrna的细胞表达水平。与坎地沙坦共同治疗逆转了Ang II对这些mrna表达水平的抑制作用。内源性BMP-6和激活素受体样激酶-2的中和作用减弱了这种突破现象。总的来说，这些数据表明BMP-6的可用性和反应的变化可能涉及慢性ARB治疗中醛固酮抑制的细胞逃逸的发生。

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.