title: Mineralocorticoid versus glucocorticoid receptor occupancy mediating aldosterone-stimulated sodium transport in a novel renal cell line.
abstract: Aldosterone controls sodium balance by regulating an epithelial sodium channel (ENaC)-mediated sodium transport along the aldosterone-sensitive distal nephron, which expresses both mineralocorticoid (MR) and glucocorticoid receptors (GR). Mineralocorticoid specificity is ensured by 11beta-hydroxysteroid dehydrogenase type 2, which metabolizes cortisol or corticosterone into inactive metabolites that are unable to bind MR and/or GR. The fractional occupancy of MR and GR by aldosterone mediating the sodium transport response in the aldosterone-sensitive distal nephron cannot be studied in vivo. For answering this question, a novel mouse cortical collecting duct cell line (mCCD(cl1)), which expresses significant levels of MR and GR and a robust aldosterone sodium transport response, was used. Aldosterone elicited a biphasic response: Low doses (K(1/2) = approximately 0.5 nM) induced a transient and early increase of sodium transport (peaking at 3 h), whereas high doses (K(1/2) = approximately 90 nM) entailed an approximately threefold larger, long-lasting response. At 3 h, the corticosterone dose-response curve was shifted to the right compared with that of aldosterone by more than two log concentrations, an effect that was fully reverted in the presence of the 11beta-hydroxysteroid dehydrogenase type 2 inhibitor carbenoxolone. Low doses of dexamethasone (0.1 to 1 nM) failed to induce an early response, but high doses elicited a long-lasting response (K(1/2) = approximately 8 nM), similar to that observed for high aldosterone concentrations. Equilibrium binding assays showed that both aldosterone and corticosterone bind to a high-affinity, low-capacity site, whereas dexamethasone binds to one site. Within the physiologic range of aldosterone concentrations, sodium transport is predicted to be controlled by MR occupancy during circadian cycles and by MR and GR occupancy during salt restriction or acute stress.
authors.affiliation: Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland.
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Gaeggeler
authors.forename: Elena
authors.initials: E
authors.lastname: Gonzalez-Rodriguez
authors.forename: Nicole Fowler
authors.initials: NF
authors.lastname: Jaeger
authors.forename: Dominique
authors.initials: D
authors.lastname: Loffing-Cueni
authors.forename: Rikke
authors.initials: R
authors.lastname: Norregaard
authors.forename: Johannes
authors.initials: J
authors.lastname: Loffing
authors.forename: Jean-Daniel
authors.initials: JD
authors.lastname: Horisberger
authors.forename: Bernard C
authors.initials: BC
authors.lastname: Rossier
mesh_terms: D042842:11-beta-Hydroxysteroid Dehydrogenases / Q000378:metabolism; D000450:Aldosterone / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001667:Binding, Competitive; D001692:Biological Transport / Q000187:drug effects; D002461:Cell Line, Transformed; D003345:Corticosterone / Q000008:administration & dosage / Q000494:pharmacology; D003907:Dexamethasone / Q000008:administration & dosage / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005938:Glucocorticoids / Q000008:administration & dosage / Q000494:pharmacology; D007685:Kidney Tubules, Collecting / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D011965:Receptors, Glucocorticoid / Q000819:agonists / Q000378:metabolism*; D018161:Receptors, Mineralocorticoid / Q000819:agonists / Q000378:metabolism*; D012964:Sodium / Q000378:metabolism*
chemical_list: D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; D018161:Receptors, Mineralocorticoid; D000450:Aldosterone; D003907:Dexamethasone; D012964:Sodium; D042842:11-beta-Hydroxysteroid Dehydrogenases; D003345:Corticosterone