Hypoxia causes down-regulation of 11 beta-hydroxysteroid dehydrogenase type 2 by induction of Egr-1.

Abstract

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.

• Authors: Christian D Heiniger, Radina M Kostadinova, Mascha K Rochat, Andreas Serra, Paolo Ferrari, Bernhard Dick, Brigitte M Frey, Felix J Frey
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 17 Issue 8 Pg. 917-9 (May 2003) ISSN: 1530-6860 [Electronic] United States
• PMID: 12626438 (Publication Type: Journal Article)

Chemical References

• DNA-Binding Proteins
• EGR1 protein, human
• Early Growth Response Protein 1
• Egr1 protein, rat
• Flavonoids
• Immediate-Early Proteins
• RNA, Messenger
• Transcription Factors
• Tetrahydrocortisone
• Antimycin A
• Tetrahydrocortisol
• Hydroxysteroid Dehydrogenases
• 11-beta-Hydroxysteroid Dehydrogenase Type 2
• HSD11B2 protein, human
• Luciferases
• 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
• Cortisone
• Hydrocortisone

Topics

• 11-beta-Hydroxysteroid Dehydrogenase Type 2
• Animals
• Antimycin A (pharmacology)
• Cell Hypoxia
• Cell Line
• Cortisone (urine)
• DNA-Binding Proteins (genetics, metabolism)
• Dose-Response Relationship, Drug
• Down-Regulation
• Early Growth Response Protein 1
• Epithelial Cells (drug effects, metabolism)
• Flavonoids (pharmacology)
• Gas Chromatography-Mass Spectrometry
• Gene Expression Regulation
• Humans
• Hydrocortisone (urine)
• Hydroxysteroid Dehydrogenases (genetics, metabolism)
• Hypoxia
• Immediate-Early Proteins
• Ischemia (physiopathology)
• Kidney (cytology, drug effects, metabolism)
• Luciferases (genetics, metabolism)
• Male
• RNA, Messenger (genetics, metabolism)
• Rats
• Tetrahydrocortisol (urine)
• Tetrahydrocortisone (urine)
• Transcription Factors (genetics, metabolism)
• Transfection