Glucocorticoid metabolism by 11-β hydroxysteroid dehydrogenase type 2 modulates human mineralocorticoid receptor transactivation activity
| Autor: | Nicolette Farman, Marie-Edith Rafestin-Oblin, Michel Fay, Françoise Cluzeaud, Brigitte Bocchi, Jérôme Fagart |
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| Rok vydání: | 2003 |
| Předmět: |
Models
Molecular Transcriptional Activation endocrine system medicine.medical_specialty Time Factors Endocrinology Diabetes and Metabolism Blotting Western Clinical Biochemistry Biology Kidney Ligands Transfection Biochemistry Partial agonist Cell Line chemistry.chemical_compound Transactivation Endocrinology Mineralocorticoid receptor Corticosterone 11-beta-Hydroxysteroid Dehydrogenase Type 2 Internal medicine medicine Animals Humans Hydroxysteroid dehydrogenase Glucocorticoids Molecular Biology Aldosterone Dose-Response Relationship Drug Activator (genetics) Hydroxysteroid Dehydrogenases Cell Biology Precipitin Tests Protein Structure Tertiary Rats Receptors Mineralocorticoid medicine.anatomical_structure Microscopy Fluorescence chemistry Molecular Medicine Plasmids Protein Binding |
| Zdroj: | The Journal of Steroid Biochemistry and Molecular Biology. 84:239-244 |
| ISSN: | 0960-0760 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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