Aldosterone (Aldo) is involved in various cardiovascular diseases such as hypertension and heart failure. Aldo levels are known to be increased in patients with polycystic ovary syndrome, and expression of the mineralocorticoid receptor (MR) has also been detected in the ovary. However, the effect of Aldo on reproductive function has yet to be elucidated. Here, we examined the effects of Aldo on follicular steroidogenesis using primary culture of rat granulosa cells by focusing on the ovarian bone morphogenetic protein (BMP) system acting as a luteinizing inhibitor. We found that Aldo treatment increased FSH-induced progesterone production in a concentration-responsive manner. Consistent with the effects on steroidogenesis, Aldo increased mRNA levels of progesterogenic factor and enzymes including StAR and P450scc, whereas Aldo failed to change FSH-induced estradiol and cAMP synthesis or P450arom expression by granulosa cells. Progesterone production and StAR expression induced by FSH and Aldo were reversed by co-treatment with spironolactone, suggesting the involvement of geonomic MR action. Aldo treatment attenuated Smad1/5/9 phosphorylation and Id1 transcription induced by BMP-6. Furthermore, Aldo enhanced the expression of inhibitory Smad6 in the presence of BMP-6. In addition, BMP-6 downregulated MR expression, while Aldo modulated the mRNA levels of endogenous BMP-6 and BMP type-II receptors, indicating the existence of a feedback loop between the BMP system and MR in granulosa cells. Collectively, the results indicated that Aldo predominantly enhances FSH-induced progesterone production by inhibiting BMP-Smad signaling, suggesting a novel role of Aldo in ovarian steroidogenesis and a functional link between MR and BMP pathways in granulosa cells.

醛固酮（Aldo）与多种心血管疾病有关，例如高血压和心力衰竭。已知多囊卵巢综合征患者的醛固酮水平升高，并且在卵巢中也检测到了盐皮质激素受体（MR）的表达。但是，Aldo对生殖功能的影响尚未阐明。在这里，我们集中于卵巢黄素形成蛋白（BMP）系统作为黄体生成抑制剂，使用大鼠颗粒细胞的原代培养检查了Aldo对卵泡类固醇生成的影响。我们发现，Aldo处理以浓度响应方式增加了FSH诱导的孕激素的产生。与对类固醇生成的影响一致，Aldo增加了孕激素和包括StAR和P450scc在内的酶的mRNA水平，而Aldo未能改变颗粒细胞FSH诱导的雌二醇和cAMP合成或P450arom表达。FSH和Aldo诱导的孕酮生成和StAR表达通过与螺内酯共同处理而逆转，表明参与了基因组MR作用。Aldo处理减弱了BMP-6诱导的Smad1 / 5/9磷酸化和Id1转录。此外，在BMP-6存在下，Aldo增强了抑制性Smad6的表达。此外，BMP-6下调了MR表达，而Aldo调节了内源性BMP-6和BMP II型受体的mRNA水平，表明颗粒细胞中BMP系统与MR之间存在反馈环。总体而言，结果表明Aldo通过抑制BMP-Smad信号传导主要增强了FSH诱导的孕激素生成，