Differences between aldosterone and its antagonists in binding kinetics and ligand-induced hsp90 release from mineralocorticosteroid receptor

Rafestin‐Oblin, Marie‐Edith; Lombès, Marc; Couette, Brigitte; Baulieu, Étienne-Émile

doi:10.1016/0960-0760(92)90430-q

Cited by 27 publications

(11 citation statements)

References 17 publications

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“…5A). As expected, a 100-fold excess of the two MR antagonists, spironolactone and RU26752 (Rafestin-Oblin et al, 1992), have a high efficiency to inhibit [ 3 H]aldosterone to MR (Fig. 5A).…”

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confidence: 94%

The Synthetic Androgen Methyltrienolone (R1881) Acts as a Potent Antagonist of the Mineralocorticoid Receptor

Takeda

Pinon²,

Bens³

et al. 2006

Mol Pharmacol

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Aldosterone binds to the mineralocorticoid receptor (MR) and exerts fine control over Na ϩ absorption in renal collecting duct cells (CCDs). Many natural and synthetic steroids can also bind to the MR to produce agonist or antagonist effects. Here, we investigate whether androgenic hormones act as MR agonist or antagonist ligands in CCDs. Testosterone (T), dihydrotestosterone (DHT), and methyltrienolone (R1881), a synthetic androgen agonist, all bind to the MR. R1881 displayed the same affinity for MR as aldosterone. Androgens did not activate the MR transiently expressed in human embryonic kidney 293T cells but did antagonize aldosterone-induced MR trans-activation activity (R1881ϾDHTϾT). Short-circuit current (I sc ) experiments, used to measure transepithelial Na ϩ transport, revealed that 10 Ϫ5 M T and DHT or R1881 prevented the increase in the amiloride-sensitive component of I sc caused by aldosterone in mouse mpkCCD cl4 collecting duct cells partially and totally, respectively. In contrast, androgens had no effect on stimulated I sc elicited by the specific glucocorticoid agonist 11␤,17␤-dihydroxy-17␣-(1-propynyl)androst-1,4,6-trien-3-one (RU26988). Docking of steroids within the crystal structure of the ligandbinding domain of MR, together with trans-activation studies, revealed that the contacts between the 17␤-hydroxyl group of androgens and the Asn770, Cys942, and Thr945 residues of the ligand-binding cavity stabilize ligand binding complexes but are not strong enough to keep the receptor in its active state. Altogether, these findings indicate that androgen ligands, particularly R1881, act as MR antagonists in aldosterone target cells and provide new insights into the requirements for MR activation to occur and for the designing of new selective MR antagonists.

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confidence: 94%

The Synthetic Androgen Methyltrienolone (R1881) Acts as a Potent Antagonist of the Mineralocorticoid Receptor

Takeda

Pinon²,

Bens³

et al. 2006

Mol Pharmacol

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“…We have found previously that progesterone is a physiological ligand for MR in sheep (35) as well as in humans (37). Progesterone shows a high affinity for MR, with only weak transactivational activity (7,32,37,41). In vitro characterization of progesterone has demonstrated that, like other MR antagonists, progesterone dissociates more rapidly from the MR than do agonists such as cortisol or aldosterone.…”

Section: Discussionmentioning

confidence: 99%

Differential effects of mineralocorticoid blockade on the hypothalamo-pituitary-adrenal axis in pregnant and nonpregnant ewes

Lingis

Richards

Keller‐Wood

2011

American Journal of Physiology-Endocrinology and Metabolism

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Lingis M, Richards EM, Keller-Wood M. Differential effects of mineralocorticoid blockade on the hypothalamo-pituitary-adrenal axis in pregnant and nonpregnant ewes. Am J Physiol Endocrinol Metab 300: E592-E599, 2011. First published January 4, 2011; doi:10.1152/ajpendo.00560.2010.-During pregnancy, plasma ACTH and cortisol are chronically increased; this appears to occur through a reset of hypothalamo-pituitary-adrenal (HPA) activity. We have hypothesized that differences in mineralocorticoid receptor activity in pregnancy may alter feedback inhibition of the HPA axis. We tested the effect of MR antagonism in pregnant and nonpregnant ewes infused for 4 h with saline or the MR antagonist canrenoate. Pregnancy significantly increased plasma ACTH, cortisol, angiotensin II, and aldosterone. Infusion of canrenoate increased plasma ACTH, cortisol, and aldosterone in both pregnant and nonpregnant ewes; however, the temporal pattern of these responses differed between these two reproductive states. In nonpregnant ewes, plasma ACTH and cortisol transiently increased at 1 h of infusion, whereas in pregnant ewes the levels gradually increased and were significantly elevated from 2 to 4 h of infusion. MR blockade increased plasma aldosterone from 2 to 4 h in the pregnant ewes but only at 4 h in the nonpregnant ewes. In both pregnant and nonpregnant ewes, the increase in plasma aldosterone was significantly related to the timing and magnitude of the increase in plasma potassium. The results indicate a differential effect of MR activity in pregnant and nonpregnant ewes and suggest that the slow changes in ACTH, cortisol, and aldosterone are likely to be related to blockade of MR effects in the kidney rather than to effects of MR blockade in hippocampus or hypothalamus.cortisol; adrenocorticotropic hormone; pregnancy; canrenoate; aldosterone IN STUDIES OF BOTH WOMEN (8) and ewes (3), basal plasma adrenocorticotropic hormone (ACTH) and cortisol have been shown to increase during pregnancy. The increase in adrenal steroid secretion is critical for normal pregnancy. Reduction of either maternal cortisol or maternal aldosterone results in alterations in maternal and fetal physiology (19 -21). We have hypothesized that there is a change in the regulation of basal ACTH in the pregnant state. Previous studies in our laboratory in adrenalectomized sheep have shown that the concentration for cortisol replacement required to normalize basal plasma ACTH is increased in pregnancy and that replacement of pregnant ewes with cortisol to plasma concentrations similar to those measured in nonpregnant ewes increases both basal and hypotension-stimulated ACTH release (23,26). On the other hand, in studies using adrenal-intact ewes, the inhibition of ACTH produced by raising plasma cortisol above resting levels is not different during pregnancy (23). Therefore, we have hypothesized that during pregnancy the "set point" of the negative feedback regulation by cortisol is increased, and/or a greater increase in cortisol is required in the pregnant s...

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“…The mineralocorticoid (MC) receptor (MCR) is the largest member in the steroid subfamily, which also contains receptors for androgens, progestins and glucocorticoids (GC), and which recognize an identical HRE with the exception of members of the estrogen receptor subfamily which recognize a different HRE [6,7]. MCR is a 8-9S heterooligomeric complex that includes the 90 kDa heat shock protein (hsp90) [9]. MC and GC hormones elicit distinct physiological responses, yet the MCR and GC receptor (GCR) bind to and activate transcription similarly from a consensus simple HRE.…”

Section: Introductionmentioning

confidence: 99%

Effects of glucocorticoids and mineralocorticoids on proliferation and maturation of human peripheral blood stem cells

Grafte-Faure¹,

Leveque²,

Vasse³

et al. 1999

Am. J. Hematol.

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It has been shown that hematopoietic progenitors can be expanded ex vivo in the presence of various cytokine combinations. Glucocorticoids (GC) are involved in the self-renewal of erythroid progenitors in chicken. To see whether GC have a similar effect on hematopoiesis in humans, CD34(+) peripheral blood stem cells were cultured in serum free medium in the presence of a GC, triamcinolone acetonide. However, our results demonstrate an inhibition of both erythroid and granulocyte-macrophage (GM) proliferation and a modification of erythroid colony morphology. Furthermore, RU38486 (Mifepristone), a potent GC antagonist, was unable to reverse the inhibitory effect of triamcinolone acetonide. We also identified and characterized another steroid subfamily, the mineralocorticoid (MC) subfamily, in human PB CD34(+) cells. The MC, aldosterone, significantly enhanced GM colony formation and diminished the erythroid colony number. Neither of effects were inhibited by ZK91587, an antagonist specific to the MC receptor (MCR). In contrast, ZK91587 reversed the stimulatory effect of deoxycorticosterone on GM colony formation. Cytoplasmic staining for MCR was observed in CD34(+) cells incubated with a polyclonal antiserum raised against human MCR. To our knowledge, this is the first demonstration of the presence of MCR in human PB CD34(+) cells.

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Differences between aldosterone and its antagonists in binding kinetics and ligand-induced hsp90 release from mineralocorticosteroid receptor

Cited by 27 publications

References 17 publications

The Synthetic Androgen Methyltrienolone (R1881) Acts as a Potent Antagonist of the Mineralocorticoid Receptor

The Synthetic Androgen Methyltrienolone (R1881) Acts as a Potent Antagonist of the Mineralocorticoid Receptor

Differential effects of mineralocorticoid blockade on the hypothalamo-pituitary-adrenal axis in pregnant and nonpregnant ewes

Effects of glucocorticoids and mineralocorticoids on proliferation and maturation of human peripheral blood stem cells

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