Department of Endocrinology and Hypertension, Tokyo Women's Medical University, Tokyo, Japan.
Department of Cardiology, Keio University School of Medicine, Tokyo, Japan; Department of Life Science and Medical Bioscience, School of Advanced Science and Engineering, Waseda University, Tokyo, Japan.
Biochem Biophys Res Commun. 2020 Mar 26;524(1):184-189. doi: 10.1016/j.bbrc.2020.01.088. Epub 2020 Jan 23.
Plasma aldosterone concentration increases in proportion to the severity of heart failure, even during treatment with renin-angiotensin system inhibitors. This study investigated alternative regulatory mechanisms of aldosterone production that are significant in heart failure. Dahl salt-sensitive rats on a high-salt diet, a rat model of heart failure with cardio-renal syndrome, had high plasma aldosterone levels and elevated β3-adrenergic receptor expression in hypoxic zona glomerulosa cells. In H295R cells (a human adrenocortical cell line), hypoxia-induced β3-adrenergic receptor expression. Hypoxia-mediated β3-adrenergic receptor expression augmented aldosterone production by facilitating hydrolysis of lipid droplets though ERK-mediated phosphorylation of hormone-sensitive lipase, also known as cholesteryl ester hydrolase. Hypoxia also accelerated the synthesis of cholesterol esters by acyl-CoA:cholesterol acyltransferase, thereby increasing the cholesterol ester content in lipid droplets. Thus, hypoxia enhanced aldosterone production by zona glomerulosa cells via promotion of the accumulation and hydrolysis of cholesterol ester in lipid droplets. In conclusion, hypoxic zona glomerulosa cells with heart failure show enhanced aldosterone production via increased catecholamine responsiveness and activation of cholesterol trafficking, irrespective of the renin-angiotensin system.
血浆醛固酮浓度与心力衰竭的严重程度成正比，即使在肾素-血管紧张素系统抑制剂治疗期间也是如此。本研究探讨了醛固酮产生的其他调节机制，这些机制在心力衰竭中很重要。高盐饮食的 Dahl 盐敏感大鼠，即伴有心肾综合征的心力衰竭大鼠模型，其血浆醛固酮水平较高，缺氧区带肾小球细胞中β3-肾上腺素能受体表达升高。在 H295R 细胞（人肾上腺皮质细胞系）中，缺氧诱导β3-肾上腺素能受体表达。缺氧介导的β3-肾上腺素能受体表达通过 ERK 介导的激素敏感脂酶（也称为胆固醇酯水解酶）磷酸化促进脂滴的水解，从而增强醛固酮的产生。缺氧还通过酰基辅酶 A：胆固醇酰基转移酶加速胆固醇酯的合成，从而增加脂滴中的胆固醇酯含量。因此，缺氧通过促进脂滴中胆固醇酯的积累和水解，增强了肾小球带细胞的醛固酮产生。总之，心力衰竭的缺氧区带肾小球细胞通过增加儿茶酚胺反应性和激活胆固醇转运来增强醛固酮的产生，而与肾素-血管紧张素系统无关。
