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This Article Full Text Full Text (PDF) All Versions of this Article: ASN.2004121110v1 16/4/878    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Gaeggeler, H.-P. Articles by Rossier, B. C. Search for Related Content PubMed PubMed Citation Articles by Gaeggeler, H.-P. Articles by Rossier, B. C.

Mineralocorticoid versus Glucocorticoid Receptor Occupancy Mediating Aldosterone-Stimulated Sodium Transport in a Novel Renal Cell Line

Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland

Address correspondence to: Dr. Bernard C. Rossier, Département de pharmacologie et de toxicologie, Université de Lausanne, Rue du Bugnon 27, CH-1005 Lausanne, Switzerland. Phone: +4121-692-5351; Fax: +4121-692-5355; E-mail: Bernard.Rossier{at}unil.ch

Received for publication December 21, 2004. Accepted for publication January 22, 2005.

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 11-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 11-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.

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