Developmental and glucocorticoid regulation of pituitary 11 β-hydroxysteroid dehydrogenase 1 gene expression in the ovine fetus and lamb

Yang, Kaiping; Matthews, Stephen G.; Challis, J. R. G.

doi:10.1677/jme.0.0140109

Cited by 28 publications

(10 citation statements)

References 12 publications

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“…Unfortunately, we were not able to study the enzyme activity in the same tissues because they had been stored for an extensive period of time and most of them were no longer available at the time of this study, although all the RNA samples were well preserved. It is noteworthy that there is a tight correlation between mRNA and enzyme activity for 11 P-HSD1 in previous studies from our laboratory [7,22,23].…”

Section: Discussionmentioning

confidence: 56%

Pattern of 11β-Hydroxysteroid Dehydrogenase Type 1 Messenger Ribonucleic Acid Expression in the Ovine Uterus during the Estrous Cycle and Pregnancy1

Yang

Fraser

et al. 1996

Biology of Reproduction

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The present study was designed to examine the pattern and cellular localization of 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD1) gene expression in the ovine uterus during pregnancy and at 3 mo postpartum. High levels of 11 beta-HSD1 mRNA were detected in the endometrium from Days 60 to 143 (term = 145 days), and the levels did not change significantly during that time. The level of 11 beta-HSD1 mRNA in the endometrium was always much higher than that in the myometrium, in which the mRNA was not readily detectable throughout pregnancy; at 3 mo postpartum, 11 beta-HSD1 mRNA became undetectable in both endometrium and myometrium. Within the endometrium, intense immunoreactive 11 beta-HSD1 was localized exclusively to the luminal epithelium, and the intensity of 11 beta-HSD1 immunostaining closely followed the level of 11 beta-HSD1 mRNA. To determine whether the level of endometrial 11 beta-HSD1 mRNA was related to the status of ovarian function, tissues from non-pregnant animals at different stages of their reproductive cycle were also examined. It was found that 11 beta-HSD1 mRNA was undetectable in the endometrium of cycling animals up to Day 9 of the estrous cycle but was detectable thereafter. Taken together, these results demonstrate that within the ovine uterus the endometrium is always the dominant site of 11 beta-HSD1 gene expression in relation to the myometrium. Furthermore, the expression of 11 beta-HSD1 mRNA in the endometrium is closely related to the status of the reproductive cycle. The mRNA for 11 beta-HSD1 is highly expressed only during pregnancy and in non-pregnant animals during the late luteal phase. Since circulating levels of progesterone are elevated during both of these periods, the present findings suggest a progesterone effect on uterine 11 beta-HSD1 gene expression.

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Section: Discussionmentioning

confidence: 56%

Pattern of 11β-Hydroxysteroid Dehydrogenase Type 1 Messenger Ribonucleic Acid Expression in the Ovine Uterus during the Estrous Cycle and Pregnancy1

Yang

Fraser

et al. 1996

Biology of Reproduction

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“…Placental 11␤-HSD2 has been reported in many mammalian species including human (90, 92, 503, 553), non-human primates (44, 45), pig (350), sheep (785,787), guinea pig (608), rat (67, 104, 105, 588), and mouse (93, 127). Placental 11␤-HSD2 in the rat (588,734) and human (368,682) is localized in the syncytiotrophoblast, precisely where maternal and fetal circulations are in close proximity for transfer of nutrients and other substances.…”

Section: Localization and Ontogeny Of Placental 11␤-hsd2mentioning

confidence: 99%

11β-Hydroxysteroid Dehydrogenases: Intracellular Gate-Keepers of Tissue Glucocorticoid Action

Chapman

Holmes

Seckl

2013

Physiological Reviews

736

601

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Glucocorticoid action on target tissues is determined by the density of “nuclear” receptors and intracellular metabolism by the two isozymes of 11β-hydroxysteroid dehydrogenase (11β-HSD) which catalyze interconversion of active cortisol and corticosterone with inert cortisone and 11-dehydrocorticosterone. 11β-HSD type 1, a predominant reductase in most intact cells, catalyzes the regeneration of active glucocorticoids, thus amplifying cellular action. 11β-HSD1 is widely expressed in liver, adipose tissue, muscle, pancreatic islets, adult brain, inflammatory cells, and gonads. 11β-HSD1 is selectively elevated in adipose tissue in obesity where it contributes to metabolic complications. Similarly, 11β-HSD1 is elevated in the ageing brain where it exacerbates glucocorticoid-associated cognitive decline. Deficiency or selective inhibition of 11β-HSD1 improves multiple metabolic syndrome parameters in rodent models and human clinical trials and similarly improves cognitive function with ageing. The efficacy of inhibitors in human therapy remains unclear. 11β-HSD2 is a high-affinity dehydrogenase that inactivates glucocorticoids. In the distal nephron, 11β-HSD2 ensures that only aldosterone is an agonist at mineralocorticoid receptors (MR). 11β-HSD2 inhibition or genetic deficiency causes apparent mineralocorticoid excess and hypertension due to inappropriate glucocorticoid activation of renal MR. The placenta and fetus also highly express 11β-HSD2 which, by inactivating glucocorticoids, prevents premature maturation of fetal tissues and consequent developmental “programming.” The role of 11β-HSD2 as a marker of programming is being explored. The 11β-HSDs thus illuminate the emerging biology of intracrine control, afford important insights into human pathogenesis, and offer new tissue-restricted therapeutic avenues.

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“…The blots were washed with phosphate-buffered saline (PBS) and 0·1% Tween-20 (Sigma Chemical Co.) and incubated overnight at 4 C in blocking solution (5% skim milk powder (w/v) in PBS+Tween-20) on a mechanical shaker to block non-specific binding. Blots were incubated with primary polyclonal antibodies (ovine CBG, generated in this laboratory by Berdusco et al (1993); ovine 11 HSD1, generated by Yang et al (1995); and human GR, Affinity Bioreagents, Inc., Golden, CO, USA) diluted in 5% blocking solution (5% skim milk powder (w/v) in PBS+Tween-20) (CBG, 1:500; 11 HSD1, 1:500; GR, 5 µg/ml), for 1 h. Blots were rinsed in PBS+Tween-20 for five 5-min washes. Blots were then incubated with secondary antibodies, conjugated to horseradish peroxidase (anti-rabbit Ig horseradish peroxidase; Amersham Life Sciences, Arlington Heights, IL, USA), diluted in blocking solution (CBG, 1:2000; 11 HSD1, 1:3000; GR, 1:2000), for 1-2 h, followed by six 5-min PBS+Tween-20 washes.…”

Section: Western Blot Analysismentioning

confidence: 99%

Repeated maternal glucocorticoid administration and the developing liver in fetal sheep

Sloboda¹,

Newnham²,

Challis³

2002

Journal of Endocrinology

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Prenatal glucocorticoid exposure has been associated with a reduction in birth weight and postnatal alterations in glucose homeostasis and hypothalamic-pituitary-adrenal (HPA) axis function. The mechanisms underlying these responses are unknown, although changes in fetal hepatic development may play an important role. The fetal liver produces key regulators of fuel metabolism and of the developing HPA axis that are altered by glucocorticoids. The local availability of glucocorticoids is regulated, in part, by corticosteroid-binding protein (CBG), glucocorticoid receptors (GR) and by the enzyme 11 -hydroxysteroid dehydrogenase (11 HSD), but the effects of maternal glucocorticoid administration on the expression of these genes in the fetal liver are unknown. 11 HSD1 is the predominant form of this enzyme present in the liver and is responsible for the conversion of cortisone to cortisol. To determine if prenatal glucocorticoid exposure alters fetal hepatic regulation of CBG, 11 HSD1 and GRs, we treated pregnant ewes with betamethasone (0·5 mg/kg) intramuscularly at 104, 111 and 118 days of gestation (term 150 days). Animals were killed at 125 or 146 days of gestation. Maternal betamethasone administration did not alter mean cord plasma glucose but significantly decreased cord plasma insulin levels (P<0·05) at 125 days of gestation. At 146 days of gestation, cord plasma glucose levels were significantly increased without alterations in insulin levels following maternal betamethasone treatment (P<0·05). Maternal betamethasone administration resulted in a significant increase in fetal hepatic 11 HSD1 mRNA and protein levels at 125 days of gestation (P<0·05). CBG mRNA levels were significantly elevated over control at 125 days although levels of CBG protein were not significantly different. GR protein levels were not statistically different at either 125 or 146 days of gestation following glucocorticoid administration. These data suggest that prenatal betamethasone exposure in the ovine fetus results in alterations in cord glucose and insulin levels as well as alterations in hepatic 11 HSD1 mRNA and protein expression. These changes in 11 HSD1 increase the potential to generate local cortisol from circulating cortisone. We speculate that this could affect expression of glucocorticoid-dependent hepatic enzymes involved with the regulation of glucose production and HPA responsiveness.

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Developmental and glucocorticoid regulation of pituitary 11 β-hydroxysteroid dehydrogenase 1 gene expression in the ovine fetus and lamb

Cited by 28 publications

References 12 publications

Pattern of 11β-Hydroxysteroid Dehydrogenase Type 1 Messenger Ribonucleic Acid Expression in the Ovine Uterus during the Estrous Cycle and Pregnancy1

Pattern of 11β-Hydroxysteroid Dehydrogenase Type 1 Messenger Ribonucleic Acid Expression in the Ovine Uterus during the Estrous Cycle and Pregnancy1

11β-Hydroxysteroid Dehydrogenases: Intracellular Gate-Keepers of Tissue Glucocorticoid Action

Repeated maternal glucocorticoid administration and the developing liver in fetal sheep

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