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Glucocorticoid induction of epithelial sodium channel expression in lung and renal epithelia occurs via trans-activation of a hormone response element in the 5'-flanking region of the human epithelial sodium channel alpha subunit gene
Journal article   Open access   Peer reviewed

Glucocorticoid induction of epithelial sodium channel expression in lung and renal epithelia occurs via trans-activation of a hormone response element in the 5'-flanking region of the human epithelial sodium channel alpha subunit gene

Raouf Sayegh, Scott D Auerbach, Xiang Li, Randy W Loftus, Russell F Husted, John B Stokes and Christie P Thomas
The Journal of biological chemistry, Vol.274(18), pp.12431-12437
04/30/1999
DOI: 10.1074/jbc.274.18.12431
PMID: 10212217
url
https://doi.org/10.1074/jbc.274.18.12431View
Published (Version of record) Open Access

Abstract

In airway and renal epithelia, the glucocorticoid-mediated stimulation of amiloride-sensitive Na+ transport is associated with increased expression of the epithelial Na+ channel alpha subunit (alphaENaC). In H441 lung cells, 100 nM dexamethasone increases amiloride-sensitive short-circuit current (3.3 microA/cm2 to 7.5 microA/cm2), correlating with a 5-fold increase in alphaENaC mRNA expression that could be blocked by actinomycin D. To explore transcriptional regulation of alphaENaC, the human alphaENaC 5'-flanking region was cloned and tested in H441 cells. By deletion analysis, a approximately 150-base pair region 5' to the upstream promoter was identified that, when stimulated with 100 nM dexamethasone, increased luciferase expression 15-fold. This region, which contains two imperfect GREs, also functioned when coupled to a heterologous promoter. When individually tested, only the downstream GRE functioned in cis and bound GR in a gel mobility shift assay. In the M-1 collecting duct line Na+ transport, malphaENaC expression and luciferase expression from alphaENaC genomic fragments were also increased by 100 nM dexamethasone. In a colonic cell line, HT29, trans-activation via a heterologously expressed glucocorticoid receptor restored glucocorticoid-stimulated alphaENaC gene transcription. We conclude that glucocorticoids stimulate alphaENaC expression in kidney and lung via activation of a hormone response element in the 5'-flanking region of halphaENaC and this response, in part, is the likely basis for the up-regulation of Na+ transport in these sites.
 Cell Line Kidney Cortex - cytology Kidney Cortex - drug effects Epithelial Cells - metabolism Kidney Cortex - metabolism Epithelial Cells - drug effects Humans RNA, Messenger - genetics Transcriptional Activation - drug effects Receptors, Glucocorticoid - metabolism DNA Primers Lung - cytology RNA, Messenger - metabolism Gene Expression Regulation - drug effects Epithelial Sodium Channels Dexamethasone - pharmacology Base Sequence Lung - drug effects Amiloride - pharmacology Ion Transport Lung - metabolism Sodium Channels - genetics Tumor Cells, Cultured

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