Decreased Gene Expression of 11β-Hydroxysteroid Dehydrogenase Type 2 and 15-Hydroxyprostaglandin Dehydrogenase in Human Placenta of Patients with Preeclampsia

Schoof, Ellen; Girstl, Michaela; Frobenius, W.; Kirschbaum, Michael; Dörr, H. G.; Rascher, Wolfgang; Dötsch, J.

doi:10.1210/jcem.86.3.7311

Cited by 66 publications

(45 citation statements)

References 27 publications

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“…Cortisol has a minor inhibitory function in this process, which might be overwhelming in conditions of established pre-eclampsia, with compromised intracellular cortisol degradation by the enzyme 11-hydroxysteroid dehydrogenase type 2, as has been previously reported (29,30). Inappropriate aldosterone availability could thus be of clinical interest and supplementation by artificial mineralocorticoid agonistic drugs, such as fludrocortisone might enhance PlGF in conditions of critically low availability.…”

Section: Discussionmentioning

confidence: 88%

Placental expression of the angiogenic placental growth factor is stimulated by both aldosterone and simulated starvation

et al. 2016

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Section: Discussionmentioning

confidence: 88%

Placental expression of the angiogenic placental growth factor is stimulated by both aldosterone and simulated starvation

et al. 2016

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“…Activity is reduced in human pregnancies complicated by preeclampsia (42, 448), in association with increased cortisol in cord blood, suggesting increased fetal exposure to maternal (and/or fetal) glucocorticoids. Similarly, placental 11␤-HSD2 is decreased in fetuses with intrauterine growth retardation (176,455,619,634,718,733), perhaps a mechanism to increase fetal glucocorticoid exposure to optimize maturation in preparation for birth, trading off against growth (334). Low placental 11␤-HSD2 in IUGR correlates inversely with catch-up growth (718), a marker of programming risk (187).…”

Section: Pathogenesis and Placental 11␤-hsd2mentioning

confidence: 99%

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

Chapman

Holmes

Seckl

2013

Physiological Reviews

734

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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“…Placental lesions such as arteriolopathy, hypermaturity of villi, intervillous thrombi, and central infarction are more frequent and severe in preeclampsia, a disease characterized by hypertension and renal damage with proteinuria (22)(23)(24). Placental ischemia and inflammatory responses during preeclampsia and increased shear stress lead to the release of ATP (9,(25)(26)(27).…”

mentioning

confidence: 99%

“…The reduction of 11␤-HSD2 activity in the presence of high ATP levels observed in preeclampsia (22,23) prompted us to determine whether ATP might contribute to a reduced 11␤-HSD2 activity in trophoblasts and to elucidate whether intact cells are needed to modulate the 11␤-HSD2 activity by extracellular mononucleotides. To explore this hypothesis, we investigated the well-characterized human choriocarcinoma cell line JEG-3 displaying endothelial properties and two cell lines with epithelial features: LLCPK1, a renal tubular, and SW620, a human colonic cell line.…”

mentioning

confidence: 99%

Extracellular ATP Determines 11β-Hydroxysteroid Dehydrogenase Type 2 Activity via Purinergic Receptors

Kadereit

Fustier²,

Shojaati³

et al. 2005

Journal of the American Society of Nephrology

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Hypertension and sodium retention are features of a diminished 11␤-hydroxysteroid dehydrogenase type 2 (11␤-HSD2). The activity of this enzyme is reduced in various disease states with abnormal renal sodium retention and hypertension, including preeclampsia. ATP release to the extracellular compartment is observed with shear stress, inflammation, and placental ischemia. It was hypothesized that ATP downregulates 11␤-HSD2 activity. For that purpose, cell lines from different tissues that previously were used to study the regulation of 11␤-HSD2 were investigated: JEG-3, a vascular trophoblastic; LLCPK1, a renal tubular; and SW620, a colonic epithelial cell line. The 11␤-HSD2 activity, assessed by the conversion of 3 H-cortisol to cortisone, was reversibly reduced during incubation with ATP or its stable analogue ATP␥S in intact JEG-3 and LLCPK1, but not in SW620 cells. In JEG-3 cells, the purinergic antagonist pyridoxalphosphate-6-azophenyl-2,4-disulphonic acid but not suramin reversed the inhibition. Incubation with UTP and ADP and their degradation products including adenosine and ␣,␤-methylene-ATP did not inhibit 11␤-HSD2 activity. In contrast, 11␤-HSD2 activity increased almost 2.5-fold after incubation with 2-methylthio-ATP. This indicates a bidirectional regulation by nucleotides via purinergic receptors. In JEG-3 cells, ATP/ATP␥S did not alter 11␤-HSD2 promoter activity but reduced 11␤-HSD2 protein and mRNA concentration and half-life, suggesting a posttranscriptional regulation. In conclusion, ATP inhibits cell type specifically via purinergic receptors the expression and activity of the 11␤-HSD2 by a posttranscriptional mechanism.

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Decreased Gene Expression of 11β-Hydroxysteroid Dehydrogenase Type 2 and 15-Hydroxyprostaglandin Dehydrogenase in Human Placenta of Patients with Preeclampsia

Cited by 66 publications

References 27 publications

Placental expression of the angiogenic placental growth factor is stimulated by both aldosterone and simulated starvation

Placental expression of the angiogenic placental growth factor is stimulated by both aldosterone and simulated starvation

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

Extracellular ATP Determines 11β-Hydroxysteroid Dehydrogenase Type 2 Activity via Purinergic Receptors

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