Does Maternal Aldosterone Regulate Placental 11-Beta Hydroxysteroid Dehydrogenase Expression in Rats?
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Proper glucocorticoid exposure in utero is vital for normal fetal organ growth and maturation. The placental enzyme, 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2), plays a pivotal role in controlling fetal exposure to high levels of maternal glucocorticoid by converting cortisol into its inactive metabolite, cortisone. The present study was designed to determine whether glucocorticoids auto-regulate 11beta-HSD2 in the human placenta using cultured trophoblast cells as a model system. Trophoblasts were isolated from uncomplicated term placentas and treated with glucocorticoids. The synthetic glucocorticoid dexamethasone increased 11beta-HSD2 activity in a time- and concentration-dependent manner; this effect was accompanied by a corresponding increase in 11beta-HSD2 mRNA. Furthermore, the glucocorticoid receptor antagonist, RU-486, abrogated the dexamethasone-induced increase in 11beta-HSD2 activity, suggesting that the effect of dexamethasone is mediated through the glucocorticoid receptor. Results from transient transfection and mRNA decay experiments indicate that the glucocorticoid-induced increase in 11beta-HSD2 expression is mediated at both the transcriptional and posttranscriptional levels. In conclusion, the present study demonstrates that in cultured human trophoblasts, 11beta-HSD2 is subject to auto-regulation by glucocorticoids. If this occurs in the human placenta in vivo, the glucocorticoid-induced up-regulation of placental 11beta-HSD2 would represent an important safeguard mechanism by which the fetus may be protected from detrimental exposure to elevated levels of maternal glucocorticoids.
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Placental 11β-hydroxysteroid dehydrogenase (11β-HSD) regulates transplacental passage of maternal glucocorticoids to the fetus and is thus a key determinant of fetal glucocorticoid levels. It has also been proposed that placental 11β-HSD expression may influence local glucocorticoid actions by regulating access of corticosterone to the glucocorticoid receptor (GR) or mineralocorticoid receptor (MR). Therefore, the present study used a rat model to assess whether the GR or MR are coexpressed with the two forms of 11β-HSD (types 1 and 2) in the placental labyrinth zone, the major site of maternal-fetal transfer, and in the basal zone, the primary site of placental hormone synthesis. In situ hybridization analysis was used to assess messenger RNA (mRNA) expression for the GR, MR, 11β-HSD-1, and 11β-HSD-2 in the two placental zones on days 16, 19 and 22 of pregnancy (term = day 23). Whereas expression of the GR appeared relatively unchanged in both zones at these three stages of pregnancy, that of 11β-HSD-1 clearly increased in the labyrinth zone but fell in basal zone, whereas the opposite pattern of expression was observed for 11β-HSD-2. MR expression was not detected at any stage. The pattern of placental 11β-HSD-2 mRNA expression over days 16, 19, and 22 of pregnancy was paralleled by changes in 11β-HSD-2-specific bioactivity, but despite clear expression of 11β-HSD-1 mRNA, no bioactivity attributable to this enzyme was measurable in either placental zone. To assess the role of fetal adrenal maturation on these changes in 11β-HSD, two experimental models, maternal adrenalectomy and fetectomy, were employed. Maternal adrenalectomy on day 13 advanced maturation of the fetal adrenal cortex but had no effect on 11β-HSD-2 bioactivity in either of the placental zones at day 19. Placental 11β-HSD-2 bioactivity on day 22 was also unaffected by fetectomy 3 or 6 days earlier. In conclusion, the consistent expression of the GR in the two placental zones late in pregnancy suggests that concomitant and marked changes in 11β-HSD-1 and 11β-HSD-2 expression could have a major influence on glucocorticoid action in the placenta at this time. Moreover, the changes in 11β-HSD expression appear to be unrelated to development of the fetal adrenal cortex and are likely to reduce the placental glucocorticoid barrier near the end of pregnancy.
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The effects of gonadal hormones (GH) on angiotensin II (Ang II)‐induced hypertension (HT) have been widely studied, but little is known about the independent effects of the sex chromosome complement (SCC). HT is attenuated in young female (F) mice as compared to males (M). Reduced activity of the renal enzyme, 11β HSD‐2, is associated with altered corticosteroid activity and increased HT. We hypothesized GH and SCC may regulate renal 11β HSD‐2 activity and contribute to sex differences in Ang II‐induced HT. M and F C57BL mice were infused with vehicle (C) or Ang II (A, 800 ng/kg·bw/min) for 10 days (n = 6/group). Western blotting revealed that Ang II infusion and M sex significantly reduced 11β HSD‐2 protein (2‐way ANOVA for treatment, p = 0.034 and sex, p = 0.003). Band densities were (% MC): 100 ± 10 (MC); 140 ± 12 (FC); 84 ± 7 (MA); 109 ± 7 (FA). To determine the role of the SCC (XX or XY) independent of GH, we also conducted experiments in Sry transgenic mice whose phenotypic sex is separated from SCC by translocation of the testes‐determining gene, Sry onto an autosome. In these ovariectomized (OVX) and castrated (CAS) mice, the XX SCC was associated with significantly greater HT (153 vs. 144 mm Hg with Ang II infusion) and significantly reduced renal 11β HSD‐2 abundance. Band densities were (% Ovx XX): 100 ± 8 (Ovx XX); 122 ± 7 (Ovx XY); 96 ± 9 (Cas XX); 121 ± 11 (Cas XY). Thus, young, intact F mice have increased 11β HSD‐2 levels due to actions of GH that oppose the SCC. The HT‐promoting effects of the XX SCC may become more apparent with age as GH levels decrease. NIH‐support
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This study investigated the effects of acute and chronic restraint stress during the third week of pregnancy on placental 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) activity in rats. Acute exposure to stress on gestational day 20 immediately up-regulated placental 11beta-HSD2 activity by 160%, while chronic stress from day 14 to day 19 of pregnancy did not significantly alter basal 11beta-HSD2 activity. However, the latter reduced the capacity to up-regulate placental 11beta-HSD2 activity in the face of an acute stressor by 90%. Thus, immediate up-regulation of 11beta-HSD2, the feto-placental barrier to maternal corticosteroids, may protect the fetus against stress-induced high levels of maternal corticosteroids, but exposure to chronic stress greatly diminishes this protection.
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Chronic Stress
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Corticosterone
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Aldosterone synthase
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