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Dexamethasone regulates a noncanonical hormone response element in the endothelin‐1 (edn1) gene
Author(s) -
Stow Lisa R,
Gumz Michelle L,
Voren George E,
Wingo Charles S,
Cain Brian D
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.lb629
Subject(s) - dexamethasone , aldosterone , mineralocorticoid receptor , glucocorticoid receptor , mineralocorticoid , endocrinology , medicine , biology , steroid hormone , receptor , glucocorticoid , microbiology and biotechnology , hormone
The mineralocorticoid aldosterone stimulates edn1 mRNA in renal collecting duct (CD) cells by a mechanism involving the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR). The goal of the present study was to determine if dexamethasone, a synthetic glucocorticoid, regulated edn1 in murine inner medullary CD (mIMCD‐3) cells. Dexamethasone (1 μM) induced a 3.48±0.19 fold increase in edn1 mRNA, whereas aldosterone (1 μM) induced a 2.53±0.17 fold increase in edn1 mRNA. Similar results were obtained from mpkCCD c14 cells. RU486 inhibition of GR completely blocked dexamethasone action on edn1 . Similarly, 24h transfection of siRNA against GR blunted approximately 50% of edn1 mRNA. However, blockade of MR with either spironolactone or siRNA had no effect on dexamethasone‐induced edn1 . DNA affinity purification studies revealed that dexamethasone or aldosterone resulted in GR binding to the same hormone response element in the edn1 promoter. The edn1 hormone response element is a noncanonical sequence containing 3 binding half‐sites. Mutation analysis revealed a single high affinity half‐site that was important for both MR and GR binding. In summary, dexamethasone regulates CD edn1 expression and this interaction may be relevant for the clinical use of dexamethasone. Support by American Heart Association fellowship to LRS and NIH R01DK82680 to BDC and CSW.