The α-subunit of the epithelial sodium channel is an aldosterone-induced transcript in mammalian collecting ducts, and this transcriptional response is mediated via distinct cis-elements in the 5′-flanking region of the gene

Verity E. Mick, Omar A. Itani, Randy W. Loftus, Russell F. Husted, Thomas J. Schmidt, Christie P. Thomas

Research output: Contribution to journalArticle

101 Scopus citations

Abstract

Aldosterone stimulates Na+ reabsorption in the collecting ducts by increasing the activity of the epithelial sodium channel, ENaC. Systemic administration of aldosterone increases αENaC mRNA expression in mammalian kidney, suggesting that the αENaC gene is a target for aldosterone action in the distal nephron. To determine whether aldosterone increases αENaC gene transcription, a portion of the αENaC 5′- flanking region coupled to luciferase was transfected into MDCK-C7 cells, a collecting duct cell line with aldosterone-stimulated Na+ transport. Both dexamethasone and aldosterone stimulated αENaC-coupled reporter gene activity via the glucocorticoid receptor (GR), and this response correlated with the effect of these hormones on endogenous αENaC expression. The aldosterone-stimulated αENaC expression was blocked by actinomycin D, and aldosterone had no effect on αENaC mRNA decay, confirming a transcriptional effect. In HT-29 cells, a GR/mineralocorticoid receptor (MR)-deficient colonic cell line with constitutive αENaC expression, cotransfection with GR or MR restored aldosterone-stimulated αENaC gene transcription, although aldosterone had a functional preference for MR. Analysis of deletion constructs confirmed that a single imperfect glucocorticoid response element (GRE) is necessary and sufficient to confer the aldosterone responsiveness to the αENaC gene promoter in MDCK-C7 and HT-29 cells. These results confirm that αENaC is an aldosterone-induced transcript in the collecting duct and delineates the molecular mechanism for this effect.

Original languageEnglish
Pages (from-to)575-588
Number of pages14
JournalMolecular Endocrinology
Volume15
Issue number4
DOIs
StatePublished - Apr 30 2001
Externally publishedYes

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