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
11beta-hydroxysteroid dehydrogenase (11beta-HSD2)
enzyme, a crucial prereceptor gatekeeper for renal glucocorticosteroid-mediated
mineralocorticoid action. The effect of
hypoxia was assessed in vitro by incubating LLC-PK1 cells with
antimycin A, an inhibitor of mitochondrial oxidative phosphorylation.
Antimycin A induced a dose- and time-dependent reduction of
11beta-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
11beta-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
11beta-HSD2 activity in LLC-PK1 cells, indicating that MAPK ERK is involved in the regulation of
11beta-HSD2 in vitro. In vivo experiments in rats revealed that Egr-1
protein increases, whereas
11beta-HSD2 mRNA decreases, in kidney tissue after unilateral renal
ischemia and in humans the renal activity of
11beta-HSD2 as assessed by the urinary ratio of (tetrahydrocortisol+5alpha-
tetrahydrocortisol)/
tetrahydrocortisone declined when volunteers were exposed to
hypoxemia at high altitude up to 7000 m. Thus,
hypoxia decreases
11beta-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.