醛固酮
钙调神经磷酸酶
内分泌学
内科学
盐皮质激素
肾小球带
醛固酮合酶
甾体11β-羟化酶
化学
脱磷
细胞生物学
生物
磷酸化
磷酸酶
医学
激素
肾素-血管紧张素系统
类固醇
血管紧张素II
移植
血压
作者
Mesut Berber,Sining Leng,Agnieszka Wengi,Denise V. Winter,Alex Odermatt,Felix Beuschlein,Johannes Loffing,David T. Breault,David Pentón
出处
期刊:JCI insight
[American Society for Clinical Investigation]
日期:2023-06-13
卷期号:8 (14)
被引量:11
标识
DOI:10.1172/jci.insight.157027
摘要
The mineralocorticoid aldosterone, secreted by the adrenal zona glomerulosa (ZG), is critical for life, maintaining ion homeostasis and blood pressure. Therapeutic inhibition of protein phosphatase 3 (calcineurin, Cn) results in inappropriately low plasma aldosterone levels despite concomitant hyperkalemia and hyperreninemia. We tested the hypothesis that Cn participates in the signal transduction pathway regulating aldosterone synthesis. Inhibition of Cn with tacrolimus abolished the potassium-stimulated (K+-stimulated) expression of aldosterone synthase, encoded by CYP11B2, in the NCI-H295R human adrenocortical cell line as well as ex vivo in mouse and human adrenal tissue. ZG-specific deletion of the regulatory Cn subunit CnB1 diminished Cyp11b2 expression in vivo and disrupted K+-mediated aldosterone synthesis. Phosphoproteomics analysis identified nuclear factor of activated T cells, cytoplasmic 4 (NFATC4), as a target for Cn-mediated dephosphorylation. Deletion of NFATC4 impaired K+-dependent stimulation of CYP11B2 expression and aldosterone production while expression of a constitutively active form of NFATC4 increased expression of CYP11B2 in NCI-H295R cells. Chromatin immunoprecipitation revealed NFATC4 directly regulated CYP11B2 expression. Thus, Cn controls aldosterone production via the Cn/NFATC4 pathway. Inhibition of Cn/NFATC4 signaling may explain low plasma aldosterone levels and hyperkalemia in patients treated with tacrolimus, and the Cn/NFATC4 pathway may provide novel molecular targets to treat primary aldosteronism.
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