Evidence for compromised aldosterone synthase enzyme activity in preeclampsia.
BACKGROUND
In normal pregnancy, an increased aldosterone (Aldo) concentration coincides with volume expansion. In preeclampsia, Aldo levels are low despite intravascular volume depletion. The present investigation aimed to characterize the compromised Aldo synthesis in preeclampsia, and to identify the molecular basis hereof.


METHODS
We recruited 66 pregnant women (24 uneventful, 42 preeclamptic). Genomic DNA was isolated from peripheral blood leukocytes. Urine samples were obtained for gas chromatography-mass spectroscopic measurements of steroid hormones reflecting apparent Aldo synthase (CYP11B2) and 11-hydroxylase (CYP11B1) activities. Polymerase chain reaction (PCR)-based screening for CYP11B2 mutations was performed by SSCP, restriction analysis, and sequencing.


RESULTS
CYP11B1 activity was unaltered, but reduction of mean tetrahydro (TH)-Aldo excretion by a factor of 3.9 indicated a diminished CYP11B2 activity in preeclampsia. Accordingly, the ratios of (TH-11-dehydrocorticosterone [A]+TH-corticosterone [B]+5alpha-THB) to (TH-cortisone +TH-cortisol [F]+5alpha-THF) and of 18-OH-THA to THAldo were increased in preeclampsia 2.6- and 15.2-fold, respectively, indicating reduced Aldo synthesis due to diminished methyl oxidase (MO) activity. A lower percentage of women with normal pregnancies had CYP11B2 mutations when compared to preeclamptic women (P < 0.05). Eight polymorphisms were detected, two of which were non-amino acid conserving. Of those, the mutation V386A, earlier found to jeopardize MO activity, was exclusively observed in preeclampsia (0% vs. 17%; P < 0.05).


CONCLUSIONS
Aldo deficiency due to a compromised MO step of Aldo synthesis favors extracellular volume depletion, and may account for an increased risk of placental hypoperfusion and consecutive development of preeclampsia. The sole presence of mutation V386A in preeclamptic mothers may identify a subgroup with an increased risk to develop preeclampsia during pregnancy.
Shojaati
Kushiar
K
Division of Nephrology/Hypertension, University of Berne, Berne, Switzerland.
Causevic
Maja
M
Kadereit
Bert
B
Dick
Bernhard
B
Imobersteg
Jeanine
J
Schneider
Henning
H
Beinder
Ernst
E
Kashiwagi
Maki
M
Frey
Brigitte M
BM
Frey
Felix J
FJ
Mohaupt
Markus G
MG
D000328:Adult; D003404:Creatinine / Q000652:urine; D019405:Cytochrome P-450 CYP11B2 / Q000235:genetics* / Q000378:metabolism*; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D007962:Leukocytes / Q000502:physiology; D018807:Polymorphism, Single-Stranded Conformational; D011225:Pre-Eclampsia / Q000235:genetics* / Q000378:metabolism*; D011247:Pregnancy; D013252:Steroid 11-beta-Hydroxylase / Q000235:genetics / Q000378:metabolism; D013256:Steroids / Q000652:urine
D013256:Steroids; D003404:Creatinine; D019405:Cytochrome P-450 CYP11B2; D013252:Steroid 11-beta-Hydroxylase