Aldosterone enhances progesterone biosynthesis regulated by bone morphogenetic protein in rat granulosa cells

Published on Oct 1, 2020in The Journal of Steroid Biochemistry and Molecular Biology3.813
· DOI :10.1016/J.JSBMB.2020.105738
Yasuhiro Nakano3
Estimated H-index: 3
(Okayama University),
Toru Hasegawa4
Estimated H-index: 4
(Okayama University)
+ 6 AuthorsFumio Otsuka35
Estimated H-index: 35
(Okayama University)
Sources
Abstract
Abstract 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.
References32
Newest
#1Memory Mukangwa (Obihiro University of Agriculture and Veterinary Medicine)H-Index: 1
#2Koki Takizawa (Obihiro University of Agriculture and Veterinary Medicine)H-Index: 1
Last. Masafumi Tetsuka (Obihiro University of Agriculture and Veterinary Medicine)H-Index: 15
view all 5 authors...
Unlike sex steroids, mineralocorticoids have attracted limited attention in ovarian physiology. Recent studies on primates have indicated possible local synthesis and action of mineralocorticoids in the ovary. Here, we examined developmental changes in the levels of mineralocorticoids and expression of genes encoding their biosynthetic enzymes and receptor in the bovine ovary. The follicles and corpora lutea (CL) were collected from F1 heifers. Expression levels of 21alpha-hydroxylase (CYP21A2),...
3 CitationsSource
#1Chiara Sabbadin (UNIPD: University of Padua)H-Index: 13
#2Alessandra Andrisani (UNIPD: University of Padua)H-Index: 18
Last. Decio Armanini (UNIPD: University of Padua)H-Index: 7
view all 9 authors...
Aldosterone is the main mineralocorticoid hormone, responsible of the regulation of fluid and electrolyte balance and blood pressure. It acts also as a pro-inflammatory factor responsible of an increased cardiovascular risk, independent from blood pressure values. After the discovery of mineralocorticoid receptor (MR) in mononuclear leukocytes, further studies support its role in inflammatory and even autoimmune mechanisms underlying several diseases. In particular, recent studies reported a pos...
4 CitationsSource
#1Shiho Fujita (Okayama University)H-Index: 4
#2Toru Hasegawa (Okayama University)H-Index: 4
Last. Fumio Otsuka (Okayama University)H-Index: 35
view all 10 authors...
Abstract The involvement of orexins in reproductive function has been gradually uncovered. However, the functional role of orexins in ovarian steroidogenesis remains unclear. In the present study, we investigated the effects of orexin A on ovarian steroidogenesis by using rat primary granulosa cells that express both OX1 and OX2 receptors for orexins. Treatment with orexin A enhanced progesterone, but not estradiol, biosynthesis induced by FSH, whereas it did not affect basal levels of progester...
13 CitationsSource
Background: Melatonin regulates circadian and seasonal rhythms and the activities of hormones and cytokines that are expressed in various tissues, including the ovary, in which melatonin receptors are expressed. In the ovary, follicular growth occurs as a result of complex interactions between pituitary gonadotropins and autocrine and paracrine factors, including bone morphogenetic proteins (BMPs) that are expressed in the ovary. Methods: The effects of melatonin and BMPs on steroidogenesis were...
7 CitationsSource
Abstract The bone morphogenetic protein (BMP) system in the ovary plays a physiological role as a luteinization inhibitor in growing follicles. BMP-6 secreted from oocytes and granulosa cells can exert an inhibitory effect on follicle-stimulating hormone (FSH) actions by suppressing adenylate cyclase activity downstream of the FSH receptor. The inhibition of FSH-induced progesterone production by BMP-6 is impaired by melatonin treatment in granulosa cells. Intracellular Smad signaling induced by...
8 CitationsSource
#1Yuki Nishiyama (Okayama University)H-Index: 6
#2Toru Hasegawa (Okayama University)H-Index: 4
Last. Fumio Otsuka (Okayama University)H-Index: 35
view all 9 authors...
Abstract The effects of incretins on ovarian steroidogenesis have not been clarified. In this study, we investigated the effects of incretins, including GIP and GLP-1, on ovarian steroidogenesis using rat primary granulosa cells. Treatment with incretins significantly suppressed progesterone synthesis in the presence of FSH, and the effect of GIP was more potent than that of GLP-1. In contrast, incretins had no significant effect on estrogen synthesis by rat granulosa cells. In accordance with t...
12 CitationsSource
#1Toru HasegawaH-Index: 4
#2Yasuhiko KamadaH-Index: 15
Last. Fumio Otsuka (Okayama University)H-Index: 35
view all 8 authors...
Abstract Excess androgen and insulin-like growth factor (IGF)-I in the ovarian follicle has been suggested to be involved in the pathophysiology of polycystic ovary syndrome (PCOS). Here we investigated the impact of androgen and IGF-I on the regulatory mechanism of ovarian steroidogenesis using rat primary granulosa cells. It was revealed that androgen treatment with dihydrotestosterone (DHT) amplified progesterone synthesis in the presence of FSH and IGF-I, whereas it had no significant effect...
21 CitationsSource
#1Ayelen Noelia Amweg (CONICET: National Scientific and Technical Research Council)H-Index: 9
#2Fernanda Mariel Rodríguez (CONICET: National Scientific and Technical Research Council)H-Index: 10
Last. Hugo Hector Ortega (CONICET: National Scientific and Technical Research Council)H-Index: 25
view all 9 authors...
: Glucocorticoids (GCs) such as cortisol and corticosterone are important steroid hormones with different functions in intermediate metabolism, development, cell differentiation, immune response and reproduction. In response to physiological and immunological stress, adrenocorticotropic hormone (ACTH) acts on the adrenal gland by stimulating the synthesis and secretion of GCs. However, there is increasing evidence that GCs may also be synthesized by extra-adrenal tissues. Here, we examined the g...
8 CitationsSource
#1Ross D. Feldman (MUN: Memorial University of Newfoundland)H-Index: 56
#2Lee E. Limbird (Fisk University)H-Index: 60
Although the rapid effects of steroids, such as estrogen and aldosterone, were postulated originally to be nongenomic, it is now appreciated that activation of such signaling pathways via a steroid-acting G protein–coupled receptor, the G protein estrogen receptor (GPER), has important transcription-dependent outcomes in the regulation of cell growth and programmed cell death secondary to GPER-regulated second-messenger pathways. GPER is expressed ubiquitously and has diverse biological effects,...
51 CitationsSource
#1Kirsty A Walters (USYD: University of Sydney)H-Index: 24
Androgens mediate their actions via the androgen receptor (AR), a member of the nuclear receptor superfamily. AR-mediated androgen action is essential in male reproductive development and function; however, only in the last decade has the suspected but unproven role for AR-mediated actions in female reproduction been firmly established. Deciphering the specific roles and precise pathways by which AR-mediated actions regulate ovarian function has been hindered by confusion on how to interpret res...
74 CitationsSource
Cited By1
Newest
#1Chiaki Kashino (Okayama University)H-Index: 1
#2Toru Hasegawa (Okayama University)H-Index: 4
Last. Fumio Otsuka (Okayama University)H-Index: 35
view all 8 authors...
To elucidate the impact of glucocorticoids on ovarian steroidogenesis and its molecular mechanism by focusing on bone morphogenetic proteins (BMPs), we examined the effect of dexamethasone (Dex) on estradiol and progesterone synthesis by using primary culture of rat granulosa cells. It was revealed that Dex treatment dose-dependently decreased estradiol production but increased progesterone production induced by follicle-stimulating hormone (FSH) by granulosa cells. In accordance with the effect...
Source