Characterization of human trophoblast as a mineralocorticoid target tissue.
In mineralocorticoid target tissues, 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) confers mineralocorticoid receptor selectivity by metabolizing hormonally active cortisol to inactive cortisone, allowing aldosterone access to the receptor. This enzyme is also expressed in high abundance in fetal tissues, particularly in placental trophoblast, where a role has been proposed in regulating fetal growth and development by protecting the fetus from maternal hypercortisolaemia and modulating local glucocorticoid receptor (GR), rather than mineralocorticoid receptor-mediated responses. As such the placenta has not been considered a mineralocorticoid target tissue. We have used conventional RT-PCR and real-time quantitative RT-PCR to demonstrate that primary cultures of term human cytotrophoblast express the mineralocorticoid-responsive genes Na/K-ATPase (alpha1 and beta1 subunits), epithelial sodium channel (ENaC, alpha and gamma subunits) and the serum and glucocorticoid-inducible kinase (SGK). SGK expression was found to be rapidly and strongly induced by corticosteroids (24- and 38-fold by 10(-7) mol/l aldosterone and 10(-7) mol/l dexamethasone respectively after 1 h). Dexamethasone-, but not aldosterone-stimulated SGK induction was inhibited by GR antagonist (RU38486), confirming the presence of a functional mineralocorticoid receptor and suggesting that placental trophoblast expresses a functional mineralocorticoid receptor, which is in part responsible for the corticosteroid regulation of SGK expression. Placental 11beta-HSD2 may protect the MR in a fashion analogous to classical mineralocorticoid tissues to modulate trophoblast sodium transport.
Driver
P M
PM
Division of Medical Sciences and Fetal Medicine, University of Birmingham, Queen Elizabeth Hospital, Edgbaston, Birmingham B15 2TH, UK.
Rauz
S
S
Walker
E A
EA
Hewison
M
M
Kilby
M D
MD
Stewart
P M
PM
D000328:Adult; D053503:Epithelial Sodium Channels; D005260:Female; D006801:Humans; D017874:Immediate-Early Proteins; D008901:Mineralocorticoids / Q000494:pharmacology* / Q000502:physiology; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D012313:RNA / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000235:genetics / Q000378:metabolism; D014327:Trophoblasts / Q000737:chemistry / Q000201:enzymology / Q000378:metabolism*; D000099184:Serum-Glucocorticoid Regulated Kinases
D053503:Epithelial Sodium Channels; D017874:Immediate-Early Proteins; D008901:Mineralocorticoids; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D012313:RNA; D015222:Sodium Channels; D000254:Sodium-Potassium-Exchanging ATPase; D000099184:Serum-Glucocorticoid Regulated Kinases