Angiotensin II regulates 11beta-hydroxysteroid dehydrogenase type 2 via AT2 receptors.
BACKGROUND
In preeclampsia, cortisol degradation by the enzyme 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) is compromised, which enhances intracellular cortisol availability. This leads to vasoconstriction and renal sodium retention with volume expansion, thus increasing blood pressure. An augmented availability of angiotensin II (Ang II) predisposes to preeclampsia. Some effects of Ang II are mediated by the mitogen-activated protein kinase (MAPK) cascade, which also regulates 11beta-HSD2 activity. Therefore, we hypothesized that Ang II regulates 11beta-HSD2.


METHODS
The human choriocarcinoma cell line JEG-3, which expresses the 11beta-HSD2 isoenzyme, was used. 3H-cortisol/cortisone conversion assays and mRNA analyses by reverse transcription-polymerase chain reaction (RT-PCR) were performed. Cells were stimulated with Ang II and the effect was modulated by Ang II type 1 (AT1) and AT2 receptor blockers DUP753 or L-158809 and PD-123319, respectively. In order to elucidate the signaling cascade, the MAPK kinase inhibitors PD-098059 and U-0126 were probed. The impact of a modulated 11beta-HSD2 activity was assessed by determining the effect of cortisol on AT1 receptor mRNA.


RESULTS
Ang II reduced mRNA and activity of 11beta-HSD2 mainly by a post-transcriptional mechanism. This Ang II effect was abrogated by AT2, but not by AT1 receptor blockade. Mitogen-activated protein (MAP) kinase kinase (MAPKK) inhibitors reversed the Ang II effect. Dexamethasone augmented the mRNA expression of AT1 receptors. Cortisol enhanced AT1 receptor mRNA expression when the 11beta-HSD2 activity was reduced either by Ang II or by glycyrrhetinic acid, an 11beta-HSD2 inhibitor.


CONCLUSIONS
Ang II decreases the activity of 11beta-HSD2 by an AT2 receptor- and MAPK-dependent mechanism. The decreased activity of 11beta-HSD2 increases the intracellular availability of cortisol, which might be relevant for the pathogenesis of hypertension and preeclampsia.
Lanz
Bettina
B
Division of Nephrology/Hypertension, University of Berne, Berne, Switzerland.
Kadereit
Bert
B
Ernst
Samuel
S
Shojaati
Kushiar
K
Causevic
Maja
M
Frey
Brigitte M
BM
Frey
Felix J
FJ
Mohaupt
Markus G
MG
D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 / Q000037:antagonists & inhibitors* / Q000235:genetics; D000804:Angiotensin II / Q000494:pharmacology / Q000502:physiology*; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020871:RNA Stability / Q000187:drug effects; D012333:RNA, Messenger / Q000037:antagonists & inhibitors; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D044139:Receptor, Angiotensin, Type 2 / Q000378:metabolism*; D015398:Signal Transduction
D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D000804:Angiotensin II; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; D020929:Mitogen-Activated Protein Kinase Kinases