11β-Hydroxysteroid dehydrogenase type 2 in pregnancy and preeclampsia

Causevic, Maja; Mohaupt, Markus

doi:10.1016/j.mam.2007.04.003

Cited by 59 publications

(53 citation statements)

References 36 publications

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“…The impact of glucocorticoid excess on placental oxidative stress is of particular interest since previous studies show that dexamethasone increases plasma F 2 -isoprostane concentrations in nonpregnant rats [28]. Moreover, in pregnancy pathologies characterized by increased placental oxidative stress (i.e., PE and IUGR), placental glucocorticoid exposure is thought to be elevated because of lower 11b-hydroxysteroid dehydrogenase type 2 expression [18,19]. In the present study, however, we found no evidence of increased placental oxidative damage after dexamethasone treatment (i.e., no change in F 2 isoprostanes, TBARS, or 8-OHdG) despite profound effects on placental and fetal growth and a marked reduction in LZ expression of Ucp2.…”

Section: Discussionmentioning

confidence: 99%

“…Placental oxidative damage was assessed by measurement of F 2 -isoprostanes and thiobarbituric acid reactive substances (TBARS), both measures of lipid peroxidation, and 8-hydroxy-2-deoxy-guanosine (8-OHdG), indicative of oxidative damage to DNA. We also assessed whether placental antioxidant defenses were compromised in a model of glucocorticoidinduced IUGR since glucocorticoids are known to increase ROS generation in other tissues [16,17] and increased placental glucocorticoid exposure occurs in both PE [18] and IUGR [19].…”

Section: Introductionmentioning

confidence: 99%

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Antioxidant Defenses in the Rat Placenta in Late Gestation: Increased Labyrinthine Expression of Superoxide Dismutases, Glutathione Peroxidase 3, and Uncoupling Protein 21

Jones

Mark

Lewis

et al. 2010

Biology of Reproduction

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Placental oxidative stress plays a key role in the pathophysiology of placenta-related disorders, most notably preeclampsia (PE) and intrauterine growth restriction (IUGR). Oxidative stress occurs when accumulation of reactive oxygen species (ROS) damages DNA, proteins and lipids, an outcome that is limited by antioxidant enzymes; mitochondrial uncoupling protein 2 (UCP2) may also limit oxidative stress by reducing ROS production. Here we characterized placental antioxidant defenses during normal gestation and following glucocorticoid-induced IUGR. Placentas were collected on Days 16 and 22 of normal rat pregnancy (term = Day 23) and at Day 22 after dexamethasone treatment from Day 13. Expression of several genes encoding antioxidant enzymes (Sod1, Sod2, Sod3, Cat, Gpx3, Txn1, Txnrd1, Txnrd2, and Txnrd3) and Ucp2 was measured by quantitative RT-PCR in the labyrinth (LZ) and junctional zones (JZ) of the placenta. Expression of Sod1 and Ucp2 mRNAs and the activity of xanthine oxidase, a source of ROS, all increased from Days 16 to 22 in both placental zones, whereas Sod2 and Gpx3 increased only in the rapidly growing LZ. In contrast, Sod3 and Txnrd1 expression fell in the LZ over this period, whereas total superoxide dismutase activity remained stable. Dexamethasone treatment reduced fetal-placental growth and LZ expression of Ucp2 but increased JZ expression of Txn1. Indices of placental oxidative damage (TBARS, F(2)-isoprostanes, and 8-OHdG) did not change with gestational age or dexamethasone, indicative of adequate antioxidant protection. Overall, our data suggest that the rat placenta is protected from oxidative stress by the dynamic zone- and stage-dependent expression of antioxidant defense genes.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Antioxidant Defenses in the Rat Placenta in Late Gestation: Increased Labyrinthine Expression of Superoxide Dismutases, Glutathione Peroxidase 3, and Uncoupling Protein 21

Jones

Mark

Lewis

et al. 2010

Biology of Reproduction

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“…In humans, increased fetal and placental glucocorticoid exposure is thought to occur in a number of clinical settings. These include maternal administration of synthetic glucocorticoids for treatment of threatened preterm delivery, and reduced placental HSD11B2 in pregnancies complicated by intrauterine growth retardation (Kajantie et al 2003) and pre-eclampsia (Causevic & Mohaupt 2007).…”

Section: Introductionmentioning

confidence: 99%

Developmental programming of adult adrenal structure and steroidogenesis: effects of fetal glucocorticoid excess and postnatal dietary omega-3 fatty acids

Waddell¹,

Bollen²,

Wyrwoll³

et al. 2010

Journal of Endocrinology

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Fetal glucocorticoid excess programs a range of detrimental outcomes in the adult phenotype, at least some of which may be due to altered adult adrenocortical function. In this study, we determined the effects of maternal dexamethasone treatment on offspring adrenal morphology and function, as well as the interactive effects of postnatal dietary omega-3 (n-3) fatty acids. This postnatal dietary intervention has been shown to alleviate many of the programming outcomes in this model, but whether this is via the effects on adrenal function is unknown. Dexamethasone acetate was administered to pregnant rats (0 . 75 mg/ml drinking water) from day 13 to term. Cross-fostered offspring were raised on either a standard or high-n-3 diet. Adrenal weight (relative to body weight) at 6 months of age was unaffected by prenatal dexamethasone, regardless of postnatal diet, and stereological analysis showed no effect of dexamethasone on the volumes of adrenal components (zona glomerulosa, zona fasciculata/ reticularis or adrenal medulla). Expression of key steroidogenic genes (Cyp11a1 and Star) was unaffected by either prenatal dexamethasone or postnatal diet. In contrast, adrenal expression of Mc2r mRNA, which encodes the ACTH receptor, was higher in offspring of dexamethasone-treated mothers, an effect partially attenuated by the Hn3 diet. Moreover, stress-induced levels of plasma and urinary corticosterone and urinary aldosterone were elevated in offspring of dexamethasone-treated mothers, indicative of enhanced adrenal responsiveness. In conclusion, this study shows that prenatal exposure to dexamethasone does not increase basal adrenocortical activity but does result in a more stress-responsive adrenal phenotype, possibly via increased Mc2r expression.

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“…11␤-HSD2 is expressed not only in the human placenta, but also several other organs, including distal nephron and colon (28,32). Although the present study has revealed the mechanisms by which HH regulates 11␤-HSD2 in human placenta, whether HH regulates 11␤-HSD2 in other tissues and whether that regulation is through the same way need to be further addressed.…”

mentioning

confidence: 80%

Up-regulation of 11β-Hydroxysteroid Dehydrogenase Type 2 Expression by Hedgehog Ligand Contributes to the Conversion of Cortisol Into Cortisone

et al. 2016

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The cortisol-inactivating enzyme 11␤-hydroxysteroid dehydrogenase type 2 (11␤-HSD2) that catalyzes the intracellular inactivation of glucocorticoids plays a pivotal role in human pregnant maintenance and normal fetal development. Given the fact that the main components of Hedgehog (HH) signaling pathway are predominantly expressed in syncytial layer of human placental villi where 11␤-HSD2 is robustly expressed, in the present study, we have investigated the potential roles and underlying mechanisms of HH signaling in 11␤-HSD2 expression. Activation of HH signaling by a variety of approaches robustly induced 11␤-HSD2 expression as well as the 11␤-HSD2 activity, whereas suppression of HH signaling significantly attenuated 11␤-HSD2 expression as well as the 11␤-HSD2 activity in both human primary cytotrophoblasts and trophoblast-like BeWo cells. Moreover, among glioma-associated oncogene (GLI) family transcriptional factors in HH signaling, knockdown of GLI2 but not GLI1 and GLI3 significantly attenuated HH-induced 11␤-HSD2 expression and activity, and overexpression of GLI2 activator alone was sufficient to induce 11␤-HSD2 expression and activity. Finally, GLI2 not only directly bound to the promoter region of gene hsd11b2 to transactivate hsd11b2 but also formed a heterodimer with RNA polymerase II, an enzyme that catalyzes the transcription of DNA to synthesize mRNAs, resulting in up-regulation of hsd11b2 gene transcription. Taken together, the present study has uncovered a hitherto uncharacterized role of HH/GLI2 signaling in 11␤-HSD2 regulation, implicating that HH signaling through GLI2 could be required for the human pregnant maintenance and fetal development. PTC1 from inhibiting the activity of SMO. Activated SMO in turn initiates a series of intracellular events that culminate in activation and nuclear localization of glioblastoma (glioma-associated oncogene [GLI]) family transcription factors, which further promotes transcription of HH-responsive genes, such as Bcl2, myc, and cyclin D as well as Ptc1 and Gli1, 2 components of the HH signaling pathway itself (3-5).As a transitory endocrine organ, human placenta is responsible for the synthesis of a number of steroid hor-

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11β-Hydroxysteroid dehydrogenase type 2 in pregnancy and preeclampsia

Cited by 59 publications

References 36 publications

Antioxidant Defenses in the Rat Placenta in Late Gestation: Increased Labyrinthine Expression of Superoxide Dismutases, Glutathione Peroxidase 3, and Uncoupling Protein 21

Antioxidant Defenses in the Rat Placenta in Late Gestation: Increased Labyrinthine Expression of Superoxide Dismutases, Glutathione Peroxidase 3, and Uncoupling Protein 21

Developmental programming of adult adrenal structure and steroidogenesis: effects of fetal glucocorticoid excess and postnatal dietary omega-3 fatty acids

Up-regulation of 11β-Hydroxysteroid Dehydrogenase Type 2 Expression by Hedgehog Ligand Contributes to the Conversion of Cortisol Into Cortisone

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