Small-Conductance Ca2+-Activated Potassium Channels Negatively Regulate Aldosterone Secretion in Human Adrenocortical Cells.
Small-Conductance Ca2+-Activated Potassium Channels Negatively Regulate Aldosterone Secretion in Human Adrenocortical Cells.
复制标题
小电导 Ca2 激活钾通道负调节人肾上腺皮质细胞中醛固酮的分泌
DOI：
10.1161/hypertensionaha.116.07094
复制
发表时间：
2016-09
期刊：
影响因子：
--
通讯作者：
Hu C
中科院分区：
文献类型：
--
作者：
Yang T;Zhang HL;Liang Q;Shi Y;Mei YA;Barrett PQ;Hu C
醛固酮在维持水和电解质平衡中起关键作用，由肾上腺皮质的球状带细胞产生。球状带细胞自主过量产生醛固酮会导致原发性醛固酮增多症。近期的临床研究强调了KCNJ5钾通道在原发性醛固酮增多症中的病理作用。我们的目的是确定小电导钙激活钾通道是否也能调节人肾上腺皮质细胞的醛固酮分泌。我们发现，小电导钙激活钾通道的原型抑制剂蜂毒明肽可降低膜电位，提高细胞内钙离子浓度，并呈剂量依赖性地增加人肾上腺皮质H295R细胞的醛固酮分泌。相比之下，小电导钙激活钾通道的激动剂1 - EBIO拮抗蜂毒明肽的作用并降低醛固酮分泌。与醛固酮产生增加相一致的是，蜂毒明肽增加了类固醇生成急性调节蛋白和醛固酮合酶的mRNA表达，它们分别控制醛固酮生物合成的早期和晚期限速步骤。此外，蜂毒明肽增加了血管紧张素II刺激的醛固酮分泌，而1 - EBIO抑制了H295R细胞中血管紧张素II和高钾刺激的醛固酮产生。这些发现得到了蜂毒明肽对急性制备的人肾上腺切片基础和血管紧张素II刺激的醛固酮分泌调节的支持。我们得出结论，小电导钙激活钾通道活性负向调节人肾上腺皮质细胞的醛固酮分泌。有必要进行基因关联研究以确定小电导钙激活钾通道2型基因的突变是否也会导致原发性醛固酮增多症中醛固酮过量。
Aldosterone, which plays a key role in maintaining water and electrolyte balance, is produced by zona glomerulosa cells of the adrenal cortex. Autonomous overproduction of aldosterone from zona glomerulosa cells causes primary hyperaldosteronism. Recent clinical studies have highlighted the pathological role of the KCNJ5 potassium channel in primary hyperaldosteronism. Our objective was to determine whether small-conductance Ca2+-activated potassium (SK) channels may also regulate aldosterone secretion in human adrenocortical cells. We found that apamin, the prototypic inhibitor of SK channels, decreased membrane voltage, raised intracellular Ca2+ and dose dependently increased aldosterone secretion from human adrenocortical H295R cells. By contrast, 1-Ethyl-2-benzimidazolinone, an agonist of SK channels, antagonized apamin’s action and decreased aldosterone secretion. Commensurate with an increase in aldosterone production, apamin increased mRNA expression of steroidogenic acute regulatory protein and aldosterone synthase that control the early and late rate-limiting steps in aldosterone biosynthesis, respectively. In addition, apamin increased angiotensin II–stimulated aldosterone secretion, whereas 1-Ethyl-2-benzimidazolinone suppressed both angiotensin II– and high K+–stimulated production of aldosterone in H295R cells. These findings were supported by apamin-modulation of basal and angiotensin II–stimulated aldosterone secretion from acutely prepared slices of human adrenals. We conclude that SK channel activity negatively regulates aldosterone secretion in human adrenocortical cells. Genetic association studies are necessary to determine whether mutations in SK channel subtype 2 genes may also drive aldosterone excess in primary hyperaldosteronism.