Hypoxia causes down-regulation of 11 beta-hydroxysteroid dehydrogenase type 2 by induction of Egr-1.
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.
Heiniger
Christian D
CD
Division of Nephrology and Hypertension, University of Berne, 3010 Berne, Switzerland.
Kostadinova
Radina M
RM
Rochat
Mascha K
MK
Serra
Andreas
A
Ferrari
Paolo
P
Dick
Bernhard
B
Frey
Brigitte M
BM
Frey
Felix J
FJ
D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; D000818:Animals; D000968:Antimycin A / Q000494:pharmacology; D015687:Cell Hypoxia; D002460:Cell Line; D003348:Cortisone / Q000652:urine; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D051766:Early Growth Response Protein 1; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D008401:Gas Chromatography-Mass Spectrometry; D005786:Gene Expression Regulation; D006801:Humans; D006854:Hydrocortisone / Q000652:urine; D006913:Hydroxysteroid Dehydrogenases / Q000235:genetics / Q000378:metabolism*; D000860:Hypoxia; D017874:Immediate-Early Proteins; D007511:Ischemia / Q000503:physiopathology; D007668:Kidney / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008297:Male; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D013760:Tetrahydrocortisol / Q000652:urine; D013761:Tetrahydrocortisone / Q000652:urine; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
D004268:DNA-Binding Proteins; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; C486110:Egr1 protein, rat; D005419:Flavonoids; D017874:Immediate-Early Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D013761:Tetrahydrocortisone; D000968:Antimycin A; D013760:Tetrahydrocortisol; D006913:Hydroxysteroid Dehydrogenases; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; C468387:HSD11B2 protein, human; D008156:Luciferases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D003348:Cortisone; D006854:Hydrocortisone