NCBI Summary:
This gene encodes the mineralocorticoid receptor, which mediates aldosterone actions on salt and water balance within restricted target cells. The protein functions as a ligand-dependent transcription factor that binds to mineralocorticoid response elements in order to transactivate target genes. Mutations in this gene cause autosomal dominant pseudohypoaldosteronism type I, a disorder characterized by urinary salt wasting. Defects in this gene are also associated with early onset hypertension with severe exacerbation in pregnancy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2009]
General function
Receptor
Comment
Cellular localization
Nuclear
Comment
Ovarian function
Steroid metabolism
Comment
Aldosterone enhances progesterone biosynthesis regulated by bone morphogenetic protein in rat granulosa cells. Nakano Y et al. (2020) 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.//////////////////
Expression regulated by
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Ovarian localization
Oocyte, Granulosa, Luteal cells
Comment
21-Hydroxylase-Derived Steroids in Follicles of Nonobese Women Undergoing Ovarian Stimulation for in Vitro Fertilization (IVF) Positively Correlate With Lipid Content of Luteinized Granulosa Cells (LGCs) as a Source of Cholesterol for Steroid Synthesis. Amin M 2014 et al.
Context: Mineralocorticoid synthesis by the nonhuman primate periovulatory follicle enhances luteinization. Whether a similar event occurs in women undergoing in vitro fertilization (IVF) is unknown. Objective: The objective of the study was to determine whether human luteinized granulosa cells (LGCs) produce mineralocorticoids derived from 21-hydroxylase activity and also express mRNA for 21-hydroxylase and the mineralocorticoid receptor. Design: This was a prospective cohort study. Setting: The study was conducted at an academic center. Patients: LGC lipid content and follicle fluid (FF) hormone analysis was performed on 27 nonobese IVF women. LGCs from six additional nonobese IVF women were used for gene expression studies. Intervention: At oocyte retrieval, FF was aspirated from the first follicle (=16 mm in size) of each ovary and pooled LGCs were collected. Main Outcome Measures: FF steroid analysis was performed by liquid chromatography-tandem mass spectrometry. LGCs were stained with lipid fluorescent dye BODIPY FL C16 to estimate lipid content by confocal microscopy as a cholesterol source for steroidogenesis in vivo. Quantitative real-time PCR was performed using LGCs to detect 21-hydroxylase and mineralocorticoid receptor mRNA expression. Pearson correlation coefficients determined associations between FF steroid levels and LGC lipid content. Results: FF levels of the 21-hydroxylase-derived steroids, 11-deoxycorticosterone 39.97, median (13.94-63.02) ng/mL] and 11-deoxycortisol [11-deoxycorticosterone, 2.07 (0.69-5.01) ng/mL], along with the 21-hydroxylase precursor 17-hydroxyprogesterone [1268.21 (493.26-3558.39) ng/mL], positively correlated with LGC lipid content (84 43 fluorescent units/sample) (P = .05, all steroids). 21-Hydroxylase and mineralocorticoid receptor mRNA expression was detected in LGCs. Conclusions: Human LGCs likely synthesize 21-hydroxylase-derived mineralocorticoids from cholesterol-containing lipid in vivo to promote postovulatory luteinization via mineralocorticoid receptor-mediated events.
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Demonstration of the Mineralocorticoid Receptor, 11{beta}-Hydroxysteroid Dehydrogenase 1 and 2, and Hexose-6-Phosphate Dehydrogenase in Rat Ovary. [Gomez-Sanchez EP et al. An immunohistochemical (IHC) survey using several monoclonal antibodies against different portions of the rat mineralocorticoid receptor (MR) molecule demonstrated significant specific MR immunoreactivity in the ovary, prompting further study of the localization of MR and determinants of extrinsic MR ligand specificity, 11ss-hydroxysteroid dehydrogenase 1 and 2 (11ss-HSD), and hexose-6-phosphate dehydrogenase (H6PDH). MR expression (real-time RT-PCR and western blot) did not differ significantly in whole rat ovaries at early diestrus, late diestrus, estrus, and a few hours after ovulation. MR immunostaining was most intense in corporal lutea cells, light to moderate in oocytes and granulosa cells, and least intense in theca cells. Light immunoreactivity for 11ss-HSD 2 occurred in most cells with some mural granulosa cells of mature follicles staining more strongly. The distribution of immunoreactivity for 11ss-HSD 1 and H6PDH required to generate NADPH, the co-factor required for reductase activity of 11ss-HSD 1, was similar, with the most intense staining in the cytoplasm of corporal lutea and theca cells and light or no staining in the granulosa and oocytes. MR function in the ovary is yet unclear, but distinct patterns of distribution of the 11ss-HSD 2, 11ss-HSD1 and H6PDH suggest that the ligand for MR activation in different cells of the ovary may be differentially regulated.
Follicle stages
Corpus luteum
Comment
High levels of mineralocorticoids in preovulatory follicular fluid could contribute to oocyte development. Sneeringer R et al. OBJECTIVE: To identify aldosterone and precursors in ovarian follicles and to relate levels of mineralocorticoids to previously described renin-angiotensin system follicular fluid content. DESIGN: Experimental. SETTING: Academic laboratory and affiliated large private practice. PATIENT(S): Women undergoing oocyte retrieval for in vitro fertilization (IVF). INTERVENTION(S): blacksquare, square, filled. MAIN OUTCOME MEASURE(S): The concentrations of mineralocorticoids were measured in plasma and follicular fluid. Granulosa cell mRNA expression and oocyte receptor content were evaluated. RESULT(S): High concentrations of preovulatory aldosterone and corticosterone were measured in follicular fluid (419.5 +/- 122.2 and 218,383 +/- 124,143 pg/mL, respectively). Increased mineralocorticoid levels are found in follicular fluid compared with in plasma and in large follicles compared with in small. Plasma aldosterone levels increase before ovulation. Granulosa cell gene expression that promotes aldosterone production and accumulation of corticosterone is increased in younger patients. Aldosterone receptors are localized to the surface of human oocytes. CONCLUSION(S): High levels of aldosterone and its precursor, corticosterone, were found in ovarian follicles. This combined with the presence of aldosterone receptors on oocytes suggests a possible role for aldosterone in oocyte development.