Aldosterone Stimulates Its Biosynthesis Via a Novel GPER-Mediated Mechanism
Aldosterone Stimulates Its Biosynthesis Via a Novel GPER-Mediated Mechanism
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DOI：
10.1210/jc.2019-00043
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发表时间：
2019-12-01
影响因子：
5.8
通讯作者：
Rossi, Gian Paolo
中科院分区：
文献类型：
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作者：
Caroccia, Brasilina;Seccia, Teresa Maria;Rossi, Gian Paolo
背景：雌激素受体β阻断后，G蛋白偶联雌激素受体（GPER）在人HAC15肾上腺皮质细胞中介导17β-雌二醇的醛固酮促分泌作用。由于 GPER 在其他细胞类型中介导不依赖盐皮质激素受体的醛固酮作用，因此我们假设醛固酮可以通过 GPER 激活调节其自身合成。 方法：在存在或不存在 Canrenone（一种盐皮质激素受体拮抗剂）和/或选择性 GPER 拮抗剂 G36 的情况下，将 HAC15 细胞暴露于醛固酮。醛固酮合酶 (CYP11B2) mRNA 和蛋白质水平的变化是研究终点。在从产生醛固酮的腺瘤 (APA) 和 GPER 沉默的 HAC15 细胞中离体获得的条带中重复了类似的实验。结果：醛固酮通过 GPER 作用，在两种模型中显着增加 CYP11B2 mRNA 和蛋白质表达（与未处理的样品相比，P < 0.001），因为这些作用被 G36 消除（P < 0.01），而不是被 Canrenone 消除。 GPER 沉默 (P < 0.01) 消除了醛固酮诱导的 CYP11B2 增加，从而证明醛固酮通过 GPER 发挥作用，增强其合成的限步线粒体酶 (CYP11B2)。血管紧张素 II 增强了 GPER 介导的醛固酮对 CYP11B2 的作用。免疫共沉淀研究为 GPER-血管紧张素 1 型受体异二聚化提供了证据。结论：我们提出，这种自分泌-旁分泌机制可以在紧急生理需要的情况下增强醛固酮的生物合成，其中肾素-血管紧张素醛固酮系统受到刺激，例如血容量不足。此外，由于 APA 过度表达 GPER，这种机制可能会导致原发性醛固酮增多症中发生的醛固酮过量，其形式似乎与血管紧张素 II 无关。
Context: The G protein-coupled estrogen receptor (GPER) mediates an aldosterone secretagogue effect of 17 beta-estradiol in human HAC15 adrenocortical cells after estrogen receptor beta blockade. Because GPER mediates mineralocorticoid receptor-independent aldosterone effects in other cell types, we hypothesized that aldosterone could modulate its own synthesis via GPER activation.Methods: HAC15 cells were exposed to aldosterone in the presence or absence of canrenone, a mineralocorticoid receptor antagonist, and/or of the selective GPER antagonist G36. Aldosterone synthase (CYP11B2) mRNA and protein levels changes were the study end points. Similar experiments were repeated in strips obtained ex vivo from aldosterone-producing adenoma (APA) and in GPER-silenced HAC15 cells.Results: Aldosterone markedly increased CYP11B2 mRNA and protein expression (vs untreated samples, P < 0.001) in both models by acting via GPER, because these effects were abolished by G36 (P < 0.01) and not by canrenone. GPER-silencing (P < 0.01) abolished the aldosterone-induced increase of CYP11B2, thus proving that aldosterone acts via GPER to augment the step-limiting mitochondrial enzyme (CYP11B2) of its synthesis. Angiotensin II potentiated the GPER-mediated effect of aldosterone on CYP11B2. Coimmunoprecipitation studies provided evidence for GPER-angiotensin type-1 receptor heterodimerization.Conclusion: We propose that this autocrine-paracrine mechanism could enhance aldosterone biosynthesis under conditions of immediate physiological need in which the renin-angiotensinaldosterone system is stimulated as, for example, hypovolemia. Moreover, as APA overexpresses GPER this mechanism could contribute to the aldosterone excess that occurs in primary aldosteronism in a seemingly autonomous fashion from angiotensin II.