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Hypoxia causes down‐regulation of 11β‐hydroxysteroid dehydrogenase type 2 by induction of Egr‐1
Author(s) -
Heiniger Christian D.,
Kostadinova Radina M.,
Rochat Mascha K.,
Serra Andreas,
Ferrari Paolo,
Dick Bernhard,
Frey Brigitte M.,
Frey Felix J.
Publication year - 2003
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/fj.02-0582fje
Subject(s) - antimycin a , medicine , hypoxia (environmental) , endocrinology , in vivo , chemistry , kidney , mineralocorticoid , biology , aldosterone , biochemistry , mitochondrion , oxygen , microbiology and biotechnology , organic chemistry
Hypoxia causes several renal tubular dysfunctions, including abnormal handling of potassium and sodium and increased blood pressure. Therefore, we investigated the impact of hypoxia on 11β‐hydroxysteroid dehydrogenase (11β‐HSD2) enzyme, a crucial prereceptor gatekeeper for renal glucocorticosteroid‐mediated mineralocorticoid action. The effect of hypoxia was assessed in vitro by incubating LLC‐PK 1 cells with antimycin A, an inhibitor of mitochondrial oxidative phosphorylation. Antimycin A induced a dose‐ and time‐dependent reduction of 11β‐HSD2 activity. The early growth response gene, Egr‐1, a gene known to be stimulated by hypoxia was investigated because of a potential Egr‐1 binding site in the promoter region of 11β‐HSD2. Antimycin A induced Egr‐1 protein and Egr‐1‐regulated luciferase gene expression. This induction was prevented with the MAPKK inhibitor PD 98059. Overexpression of Egr‐1 reduced endogenous 11β‐HSD2 activity in LLC‐PK 1 cells, indicating that MAPK ERK is involved in the regulation of 11β‐HSD2 in vitro. In vivo experiments in rats revealed that Egr‐1 protein increases, whereas 11β‐HSD2 mRNA decreases, in kidney tissue after unilateral renal ischemia and in humans the renal activity of 11β‐HSD2 as assessed by the urinary ratio of (tetrahydrocortisol+5α‐tetrahydrocortisol)/tetrahydrocortisone declined when volunteers were exposed to hypoxemia at high altitude up to 7000 m. Thus, hypoxia decreases 11β‐HSD2 transcription and activity by inducing Egr‐1 in vivo and in vitro . This mechanism might account for enhanced renal sodium retention and hypertension associated with hypoxic conditions.