Yang Tingting, Zhang Hai-Liang, Liang Qingnan, Shi Yingtang, Mei Yan-Ai, Barrett Paula Q, Hu Changlong
From the Department of Physiology and Biophysics, School of Life Sciences, Institutes of Brain Science (T.Y., Q.L., Y.-A.M., C.H.) and Department of Oncology, Shanghai Medical College (H.-L.Z.), Fudan University, China; Department of Urology, Fudan University Shanghai Cancer Center, China (H.-L.Z.); and Department of Pharmacology, University of Virginia, Charlottesville (Y.S., P.Q.B.).
Hypertension. 2016 Sep;68(3):785-95. doi: 10.1161/HYPERTENSIONAHA.116.07094. Epub 2016 Jul 18.
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 Ca(2+)-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 Ca(2+) 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.
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。最近的临床研究强调了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（SK）通道是否也能调节人肾上腺皮质细胞中的醛固酮分泌。我们发现，SK通道的典型抑制剂蜂毒明肽可降低膜电压、升高细胞内钙离子浓度，并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，SK通道激动剂1-乙基-2-苯并咪唑啉酮可拮抗蜂毒明肽的作用并减少醛固酮分泌。与醛固酮生成增加相一致，蜂毒明肽增加了分别控制醛固酮生物合成早期和晚期限速步骤的类固醇生成急性调节蛋白和醛固酮合酶的mRNA表达。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-乙基-2-苯并咪唑啉酮抑制了H295R细胞中血管紧张素II和高钾刺激的醛固酮生成。这些发现得到了蜂毒明肽对人肾上腺急性制备切片基础和血管紧张素II刺激的醛固酮分泌调节作用的支持。我们得出结论，SK通道活性对人肾上腺皮质细胞中的醛固酮分泌起负调节作用。有必要进行基因关联研究，以确定SK通道亚型2基因的突变是否也可能导致原发性醛固酮增多症中的醛固酮过量。
