Hyperaldosteronism is often associated with inappropriate aldosterone production and aldosterone synthase (Cyp11b2) expression. Normally, Cyp11b2 expression is limited to the adrenal zona glomerulosa (ZG) and regulated by angiotensin II which signals through Gq protein-coupled receptors. As cells migrate inwards, they differentiate into 11β-hydroxylase-expressing zona fasciculata (ZF) cells lacking Cyp11b2. The mechanism causing ZG-specific aldosterone biosynthesis is still unclear. We investigated the effect of chronic Gq signaling using transgenic mice with a clozapine -oxide (CNO)-activated human M3 muscarinic receptor (DREADD) coupled to Gq (hM3Dq) that was expressed throughout the adrenal cortex. CNO raised circulating aldosterone in the presence of a high sodium diet with greater response seen in females compared to males. Immunohistochemistry and transcriptomics indicated disrupted zonal Cyp11b2 expression while Wnt signaling remained unchanged. Chronic Gq-DREADD signaling also induced an intra-adrenal RAAS in CNO-treated mice. Chronic Gq signaling disrupted adrenal cortex zonal aldosterone production associated with ZF expression of Cyp11b2.

中文翻译：

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肾上腺 Gq 信号的慢性激活诱导束状带 Cyp11b2 表达和醛固酮增多症

醛固酮增多症通常与醛固酮生成和醛固酮合酶 (Cyp11b2) 表达不当有关。通常，Cyp11b2 表达仅限于肾上腺球状带 (ZG)，并受血管紧张素 II 调节，血管紧张素 II 通过 Gq 蛋白偶联受体发出信号。当细胞向内迁移时，它们分化成缺乏 Cyp11b2 的表达 11β-羟化酶的束状带 (ZF) 细胞。 ZG特异性醛固酮生物合成的机制尚不清楚。我们使用转基因小鼠研究了慢性 Gq 信号传导的影响，该小鼠的氯氮平氧化物 (CNO) 激活的人 M3 毒蕈碱受体 (DREADD) 与在整个肾上腺皮质表达的 Gq (hM3Dq) 偶联。在高钠饮食的情况下，CNO 会提高循环醛固酮，与男性相比，女性的反应更大。免疫组织化学和转录组学表明，区域性 Cyp11b2 表达受到破坏，而 Wnt 信号传导保持不变。慢性 Gq-DREADD 信号传导还在 CNO 治疗的小鼠中诱导肾上腺内 RAAS。慢性 Gq 信号传导破坏了与 Cyp11b2 的 ZF 表达相关的肾上腺皮质带状醛固酮的产生。