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The -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

Department of Internal Medicine (V.E.M., O.A.I., R.W.L., R.F.H., C.P.T.) Department of Physiology and Biophysics (T.J.S.), University of Iowa College of Medicine and the Veterans Affairs Medical Center (C.P.T.) Iowa City, Iowa 52242

Aldosterone stimulates Na⁺ reabsorption in the collecting ducts by increasing the activity of the epithelial sodium channel, ENaC. Systemic administration of aldosterone increases ENaC mRNA expression in mammalian kidney, suggesting that the ENaC gene is a target for aldosterone action in the distal nephron. To determine whether aldosterone increases ENaC gene transcription, a portion of the ENaC 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 ENaC-coupled reporter gene activity via the glucocorticoid receptor (GR), and this response correlated with the effect of these hormones on endogenous ENaC expression. The aldosterone-stimulated ENaC expression was blocked by actinomycin D, and aldosterone had no effect on ENaC mRNA decay, confirming a transcriptional effect. In HT-29 cells, a GR/mineralocorticoid receptor (MR)-deficient colonic cell line with constitutive ENaC expression, cotransfection with GR or MR restored aldosterone-stimulated ENaC 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 ENaC gene promoter in MDCK-C7 and HT-29 cells. These results confirm that ENaC is an aldosterone- induced transcript in the collecting duct and delineates the molecular mechanism for this effect.

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