Antimineralocorticoid Action of Progesterone in the Rat: Correlation of the Effect on Electrolyte Excretion and Interaction with Renal Mineralocorticoid Receptors*

Wambach, G.; Higgins, John R.

doi:10.1210/endo-102-6-1686

Cited by 87 publications

(38 citation statements)

References 9 publications

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“…The antagonistic properties of progesterone on the human, rat and sheep mineralocorticoid receptor have been previously described [9,11,12,13,14,15]. A 50% inhibition of the maximum transactivation of the mineralocorticoid receptor is caused by progesterone concentrations between 2 and 11 n M [9,16,17,18].…”

Section: Discussionmentioning

confidence: 99%

Influence of 17-Hydroxyprogesterone, Progesterone and Sex Steroids on Mineralocorticoid Receptor Transactivation in Congenital Adrenal Hyperplasia

et al. 2015

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Background: Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency leads to accumulation of steroid precursors and adrenal androgens. These steroids may have a biological effect on the steroid receptor with clinical consequences on diagnostics and treatment in CAH patients. Therefore, we analysed the effect of accumulated steroids [17-hydroxyprogesterone (17OHP), progesterone, androstenedione and testosterone] on aldosterone-mediated transactivation of the human mineralocorticoid receptor (hMR). Methods: A transactivation assay using transiently transfected COS7 cells was employed. Cells were co-transfected with hMR-cDNA, MMTV-luciferase and renilla-luciferase expression vectors. Transfected cells were incubated with six different steroid concentrations in addition to aldosterone (10^-10M). Luciferase and renilla activities were measured to quantify hMR transactivation. Results: Linear regression analysis showed statistically significant linear inhibition of transactivation of the hMR by 10^-10M aldosterone in the presence of increasing 17OHP [F(1,5) = 11.34, p = 0.019] and progesterone [F(1,5) = 11.08, p = 0.021] concentrations. In contrast, neither androstenedione nor testosterone affected hMR transactivation by aldosterone at a concentration of 10^-10M. Conclusion: Our study shows for the first time that neither androstenedione nor testosterone has a biological effect on aldosterone-mediated transactivation of the hMR. 17OHP and progesterone have an anti-mineralocorticoid effect in vitro that may clinically lead to an increased requirement of mineralocorticoids in poorly controlled CAH patients.

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Section: Discussionmentioning

confidence: 99%

Influence of 17-Hydroxyprogesterone, Progesterone and Sex Steroids on Mineralocorticoid Receptor Transactivation in Congenital Adrenal Hyperplasia

et al. 2015

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“…It has been suggested that increased cortisol concentrations in pregnancy may result from an anti-corticosteroid effect of progesterone [1]. Progesterone is known to bind to both the MR and GR with an extremely high affinity [34]and is a potent antimineralocorticoid [35, 36, 37]. Progesterone is also known to interact with the GR via a unique binding domain [38], to increase the rate of dissociation of glucocorticoids from the GR [39], and to exhibit antiglucocorticoid effects [40].…”

Section: Discussionmentioning

confidence: 99%

Differential Effects of Pregnancy on Mineralocorticoid and Glucocorticoid Receptor Availability and Immunoreactivity in Cortisol Feedback Sites

Roesch

Keller‐Wood²

1999

Neuroendocrinology

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The suppression of plasma adrenocorticotropic hormone by very low levels of cortisol is reduced in pregnant adrenalectomized ewes, suggesting that pregnancy reduces the efficacy of the high-affinity corticosteroid receptor. This study was designed to determine the effects of pregnancy on the availability, immunoreactivity, and affinity of both corticosteroid receptors: the high-affinity mineralocorticoid receptor (MR) and the lower-affinity glucocorticoid receptor (GR). Availability was measured in the hypothalamus, pituitary, hippocampus and kidney using a saturation point radioligand binding assay. GR availability was significantly decreased in hippocampal cytosols obtained from pregnant ewes, but did not significantly change in other tissues. This finding is consistent with increased GR activation due to elevated circulating concentrations of cortisol. MR availability significantly increased from undetectable levels in hippocampal cytosols obtained from nonpregnant ewes to 2.8 ± 1.6 fmol/mg protein in pregnant ewes, suggesting a reduced MR activation in the hippocampus during pregnancy. MR availability tended to be greater in other tissues during pregnancy, but these differences were not significant. The amount of immunoreactive MR (iMR) and GR (iGR) protein was estimated by quantifying Western blots. iGR significantly increased in the pituitary, but did not significantly change in other tissues. In contrast, iMR was significantly increased during pregnancy in all tissues assayed, suggesting that an increased cytosolic MR protein amount contributes to the observed increase in MR availability. Since studies suggest that progesterone is a potent anticorticosteroid, we tested for evidence of endogenous inhibition of binding to MR and/or GR during pregnancy by determining MR and GR affinity in pituitary cytosols obtained from nonpregnant and pregnant ewes. Although there was a tendency towards a decreased affinity of the MR in pregnant ewes, there was no significant change in the K_D of the pituitary MR or GR during pregnancy. We hypothesize that an alteration in activation and/or autoregulation of the MR during pregnancy, particularly in the hippocampus, may contribute to the observed changes in receptor availability and immunoreactivity and increase basal plasma cortisol levels during pregnancy.

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“…Prog activation of the MR is unexpected because Prog is an antagonist for wild-type human MR (Kagawa 1958, Wambach & Higgins 1978, Funder & Adam 1981, Rupprecht et al 1993b, Geller et al 2000, Rafestin-Oblin et al 2003, Sugimoto et al 2016. The mineralocorticoid activity of Prog for Leu-810 MR explained high blood pressure in pregnant woman with this mutant MR.…”

Section: Evolution Of the Contact Between Ser810 (Helix 5) And Ala773mentioning

confidence: 99%

“…In this regard, allosteric interactions between the A/B domain and the ligand-binding domain also are important in differences among corticosteroids in transcriptional activation of the GR (Pearce & Yamamoto 1993, Rupprecht et al 1993a, Oka et al 2015. Interestingly, Prog is an antagonist for human MR (Kagawa 1958, Wambach & Higgins 1978, Funder & Adam 1981, Rupprecht et al 1993b, Geller et al 2000, Sugimoto et al 2016.…”

Section: Introductionmentioning

confidence: 99%

30 YEARS OF THE MINERALOCORTICOID RECEPTOR: Evolution of the mineralocorticoid receptor: sequence, structure and function

Baker

Katsu

2017

Journal of Endocrinology

119

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The mineralocorticoid receptor (MR) is descended from a corticoid receptor (CR), which has descendants in lamprey and hagfish, cyclostomes (jawless fish), a taxon that evolved at the base of the vertebrate line. A distinct MR and GR first appear in cartilaginous fishes (Chondrichthyes), such as sharks, skates, rays and chimeras. Skate MR has a strong response to corticosteroids that are mineralocorticoids and glucocorticoids in humans. The half-maximal responses (EC50s) for skate MR for the mineralocorticoids aldosterone and 11-deoxycorticosterone are 0.07 nM and 0.03 nM, respectively. EC50s for the glucocorticoids cortisol and corticosterone are 1 nM and 0.09 nM, respectively. The physiological mineralocorticoid in ray-finned fish, which do not synthesize aldosterone, is not fully understood because several 3-ketosteroids, including cortisol, 11-deoxycortisol, corticosterone, 11-deoxycorticosterone and progesterone are transcriptional activators of fish MR. Further divergence of the MR and GR in terrestrial vertebrates, which synthesize aldosterone, led to emergence of aldosterone as a selective ligand for the MR. Here, we combine sequence analysis of the CR and vertebrate MRs and GRs, analysis of crystal structures of human MR and GR and data on transcriptional activation by 3-ketosteroids of wild-type and mutant MRs and GRs to investigate the evolution of selectivity for 3-ketosteroids by the MR in terrestrial vertebrates and ray-finned fish, as well as the basis for binding of some glucocorticoids by human MR and other vertebrate MRs.

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Antimineralocorticoid Action of Progesterone in the Rat: Correlation of the Effect on Electrolyte Excretion and Interaction with Renal Mineralocorticoid Receptors*

Cited by 87 publications

References 9 publications

Influence of 17-Hydroxyprogesterone, Progesterone and Sex Steroids on Mineralocorticoid Receptor Transactivation in Congenital Adrenal Hyperplasia

Influence of 17-Hydroxyprogesterone, Progesterone and Sex Steroids on Mineralocorticoid Receptor Transactivation in Congenital Adrenal Hyperplasia

Differential Effects of Pregnancy on Mineralocorticoid and Glucocorticoid Receptor Availability and Immunoreactivity in Cortisol Feedback Sites

30 YEARS OF THE MINERALOCORTICOID RECEPTOR: Evolution of the mineralocorticoid receptor: sequence, structure and function

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