title: Glucocorticoid metabolism by 11-beta hydroxysteroid dehydrogenase type 2 modulates human mineralocorticoid receptor transactivation activity.
abstract: The mineralocorticoid receptor (MR) binds aldosterone, but also glucocorticoid hormones (corticosterone in rodents, cortisol in humans), which largely prevail in the plasma. To prevent permanent and maximal occupancy of MR by glucocorticoid hormones in aldosterone-target cells, specific effects of aldosterone require metabolism of glucocorticoid hormones into 11-dehydroderivatives by 11-beta hydroxysteroid dehydrogenase (11-HSD2). We analyzed the effect of corticosterone or 11-dehydrocorticosterone (11-DHC) on the transactivation activity of the MR, transiently expressed in a new renal cell line expressing 11-HSD2. We show that, because of its metabolism by 11-HSD2, corticosterone is a poor activator of MR transactivation, except at micromolar concentrations, where the enzyme is saturated. We also show that high micromolar concentrations of 11 DHC are required to activate the MR. The weak antagonist property of 11-DHC on aldosterone-induced hMR transactivations is also documented. Such partial agonist activity of 11-DHC is discussed in the light of its positioning in a three-dimensional model of the MR ligand-binding domain.
authors.affiliation: INSERM U478, IFR02, Université Paris 7, Faculté de Médecine X. Bichat, BP 416, France.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Bocchi
authors.forename: Jerome
authors.initials: J
authors.lastname: Fagart
authors.forename: Francoise
authors.initials: F
authors.lastname: Cluzeaud
authors.forename: Michel
authors.initials: M
authors.lastname: Fay
authors.forename: Marie-Edith
authors.initials: ME
authors.lastname: Rafestin-Oblin
authors.forename: Nicolette
authors.initials: N
authors.lastname: Farman
mesh_terms: D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D003345:Corticosterone / Q000031:analogs & derivatives* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005938:Glucocorticoids / Q000378:metabolism*; D006801:Humans; D006913:Hydroxysteroid Dehydrogenases / Q000378:metabolism*; D007668:Kidney / Q000166:cytology; D008024:Ligands; D008856:Microscopy, Fluorescence; D008958:Models, Molecular; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051381:Rats; D018161:Receptors, Mineralocorticoid / Q000378:metabolism*; D013997:Time Factors; D015533:Transcriptional Activation; D014162:Transfection
chemical_list: D005938:Glucocorticoids; D008024:Ligands; D018161:Receptors, Mineralocorticoid; D006913:Hydroxysteroid Dehydrogenases; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; C468387:HSD11B2 protein, human; C003552:11-dehydrocorticosterone; D003345:Corticosterone