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ABSTRACT: Gestational trophoblastic disease (MGT) includes a wide spectrum of pathologies of the placenta, ranging from benign precancerous lesions, with gestational trophoblastic tumors. Metastases are the leading causes of death as a result of this tumor. They represent a major problem for obstetrics and for the public health system. To date, there is no predictor of the progression of molar pregnancies to gestational trophoblastic tumor (GTT). Only an unfavorable plasma hCG monitoring after evacuation of hydatidiform mole is used to diagnose a TTG. The causes of the development of this cancer are still poorly understood. Increasing data in the literature suggests a close association between the development of this tumor and poor placental vascularization during the first trimester of pregnancy. The development of the human placenta depends on a coordination between the trophoblast and endothelial cells. A disruption in the expression of angiogenic factors could contribute to uterine or extra-uterine tissue invasion by extravillous trophoblast, contributing to the development of TTG. This review sheds lights on the phenomenon of angiogenesis during normal and abnormal placentation, especially during the MGT and reports preliminary finding concerning, the variability of expression of "Endocrine Gland-Derived Vascular Endothelial Growth Factor" (EG-VEGF), a specific placental angiogenic factor, in normal and molar placentas, and the potential role of differentiated expressions of the main placental angiogenic factors in the scalability of hydatidiform moles towards a recovery or towards the development of gestational trophoblastic tumor. Deciphering the mechanisms by which the angiogenic factor influences these processes will help understand the pathophysiology of MGT and to create opportunities for early diagnosis and treatment of the latter.
Pathologie Biologie 05/2013; · 1.53 Impact Factor
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S Brouillet,
P Murthi,
P Hoffmann,
A Salomon,
F Sergent,
P De Mazancourt,
M Dakouane-Giudicelli,
M N Dieudonné,
P Rozenberg,
D Vaiman,
S Barbaux,
M Benharouga,
J-J Feige, N Alfaidy
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ABSTRACT: Identifiable causes of fetal growth restriction (FGR) account for 30 % of cases, but the remainders are idiopathic and are frequently associated with placental dysfunction. We have shown that the angiogenic factor endocrine gland-derived VEGF (EG-VEGF) and its receptors, prokineticin receptor 1 (PROKR1) and 2, (1) are abundantly expressed in human placenta, (2) are up-regulated by hypoxia, (3) control trophoblast invasion, and that EG-VEGF circulating levels are the highest during the first trimester of pregnancy, the period of important placental growth. These findings suggest that EG-VEGF/PROKR1 and 2 might be involved in normal and FGR placental development. To test this hypothesis, we used placental explants, primary trophoblast cultures, and placental and serum samples collected from FGR and age-matched control women. Our results show that (1) EG-VEGF increases trophoblast proliferation ([(3)H]-thymidine incorporation and Ki67-staining) via the homeobox-gene, HLX (2) the proliferative effect involves PROKR1 but not PROKR2, (3) EG-VEGF does not affect syncytium formation (measurement of syncytin 1 and 2 and β hCG production) (4) EG-VEGF increases the vascularization of the placental villi and insures their survival, (5) EG-VEGF, PROKR1, and PROKR2 mRNA and protein levels are significantly elevated in FGR placentas, and (6) EG-VEGF circulating levels are significantly higher in FGR patients. Altogether, our results identify EG-VEGF as a new placental growth factor acting during the first trimester of pregnancy, established its mechanism of action, and provide evidence for its deregulation in FGR. We propose that EG-VEGF/PROKR1 and 2 increases occur in FGR as a compensatory mechanism to insure proper pregnancy progress.
Cellular and Molecular Life Sciences CMLS 09/2012; · 6.57 Impact Factor
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03/2012; , ISBN: 978-953-51-0194-9
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ABSTRACT: Endocrine gland-derived vascular endothelial growth factor (EG-VEGF) is an angiogenic factor reported to be specific for endocrine tissues, including the placenta. Its biological activity is mediated via two G protein-coupled receptors, prokineticin receptor 1 (PROKR1) and prokineticin receptor 2 (PROKR2). We have recently shown that (i) EG-VEGF expression peaks between the 8th and 11th weeks of gestation, (ii) its mRNA and protein levels are up-regulated by hypoxia, (iii) EG-VEGF is a negative regulator of trophoblast invasion and (iv) its circulating levels are increased in preeclampsia (PE), the most threatening pathology of pregnancy. Here, we investigated the regulation of the expression of EG-VEGF and its receptors by hCG, a key pregnancy hormone that is also deregulated in PE. During the first trimester of pregnancy, hCG and EG-VEGF exhibit the same pattern of expression, suggesting that EG-VEGF is potentially regulated by hCG. Both placental explants (PEX) and primary cultures of trophoblasts from the first trimester of pregnancy were used to investigate this hypothesis. Our results show that (i) LHCGR, the hCG receptor, is expressed both in cyto- and syncytiotrophoblasts, (ii) hCG increases EG-VEGF, PROKR1 and PROKR2 mRNA and protein expression in a dose- and time-dependent manner, (iii) hCG increases the release of EG-VEGF from PEX conditioned media, (iv) hCG effects are transcriptional and post-transcriptional and (v) the hCG effects are mediated by cAMP via cAMP response elements present in the EG-VEGF promoter region. Altogether, these results demonstrate a new role for hCG in the regulation of EG-VEGF and its receptors, an emerging regulatory system in placental development.
Cellular and Molecular Life Sciences CMLS 12/2011; 69(9):1537-50. · 6.57 Impact Factor
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ABSTRACT: We have previously shown that in utero nicotine exposure causes impaired fertility, follicle immaturity, and ovarian dysfunction in adult female rat offspring. These characteristics overtly resemble the clinical profile of polycystic ovarian syndrome (PCOS) and recent studies have shown that thiazolidinediones such as rosiglitazone improve fertility in women with PCOS but the mechanism is not well defined. Our goal was to examine whether rosiglitazone would (1) ameliorate the altered ovarian physiology that occurs following fetal and neonatal exposure to nicotine and (2) to examine whether this could be due to normalization of ovarian vascularization. At weaning, offspring of nicotine-exposed dams were given either vehicle (NV) or rosiglitazone (3 mg kg(-1) day(-1); NR). Offspring of saline-exposed dams received vehicle (SV). Tissues were collected when the female offspring reached 26 weeks of age. NV animals had reduced granulosa cell proliferation and increased ovarian cell apoptosis. Treatment with rosiglitazone increased proliferation, and decreased apoptosis, compared NV animals. NV animals had decreased ovarian vascularity relative to controls, whereas NR animals had an intermediate level of ovarian vessel density. Moreover, ovaries from NV animals had decreased levels of the pro-angiogenic growth factors vascular endothelial growth factor (VEGF) and endocrine gland-derived VEGF both of which were increased with rosiglitazone treatment. Rosiglitazone reversed some of the nicotine effects in the ovary and increased ovarian vascularization, follicle maturation and improved oocyte competence. Rosiglitazone may be an important treatment option for PCOS and the present study provides a potential mechanism by which rosiglitazone may have beneficial effects on fertility in these patients.
Endocrine 09/2009; 36(2):281-90. · 1.42 Impact Factor
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ABSTRACT: Compelling evidence indicates that vascular endothelial growth factor (VEGF) is an important mediator of placental angiogenesis and appears to be disregulated in pre-eclampsia (PE). Recently, we characterised the expression of EG-VEGF (endocrine gland-derived vascular endothelial growth factor), also known as prokineticin 1 (PK1) in human placenta during the first trimester of pregnancy and showed that this factor is likely to play an important role in human placentation. However, because it is impossible to prospectively study placentation in humans, it has been impossible to further characterise EG-VEGF expression throughout complete gestation and especially at critical gestational ages for PE development. In the present study, we used mouse placenta to further characterise EG-VEGF expression throughout gestation. We investigated the pattern of expression of EG-VEGF and its receptors, PKR1 and PKR2 at the mRNA and protein levels. Our results show that EG-VEGF and VEGF exhibit different patterns of expression and different localisations in the mouse placenta. EG-VEGF was mainly localised in the labyrinth whereas VEGF was mainly present in glycogen and giant cells. EG-VEGF mRNA and protein levels were highest before 10.5days post coitus (dpc) whereas those of VEGF showed stable expression throughout gestation. PKR1 protein was localised to the labyrinth layer and showed the same pattern of expression as EG-VEGF whereas PKR2 expression was maintained over 10.5dpc with both trophoblastic and endothelial cell localisations. Altogether these findings suggest that EG-VEGF may have a direct effect on both endothelial and trophoblastic cells and is likely to play an important role in mouse placentation.
Placenta 11/2007; 28(10):1049-58. · 3.69 Impact Factor
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ABSTRACT: In the late-gestation sheep, increased fetal plasma cortisol concentration and placental oestradiol (E(2)) output contribute to fetal organ maturation, in addition to the onset of parturition. Both cortisol and E(2) are believed to regulate the enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), which interconverts bioactive 11-hydroxy glucocorticoids and their inactive 11-keto metabolites. 11beta-HSD1, abundantly expressed in fetal liver, operates primarily as a reductase enzyme to produce bioactive cortisol and thus regulates local hepatic glucocorticoid concentrations. Cortisol acts through the glucocorticoid receptor (GR) present in the liver. In this study, we examined the effects of cortisol and E(2) on hepatic 11beta-HSD1 and GR in the liver of chronically catheterized sheep fetuses treated with saline (n=5), cortisol (1.35 mg/h; n=5), saline+4-hydroxyandrostendione, a P450 aromatase inhibitor (4-OHA; 1.44 mg/h; n=5), or cortisol+4-OHA (n=5). Cortisol infusion resulted in increased plasma concentrations of fetal cortisol and E(2); concurrent administration of 4-OHA attenuated the increase in plasma E(2) concentrations. Using immunohistochemistry, we showed that fetal hepatocytes expressed both 11beta-HSD1 and GR proteins. Cortisol treatment increased GR in both cytosol and nuclei of hepatocytes; concurrent administration of 4-OHA was associated with distinct nuclear GR staining. Western blot revealed that cortisol, in the absence of increased E(2) concentrations, significantly increased concentrations of 11beta-HSD1 (34 kDa) and GR (95 kDa) proteins. 11beta-HSD1 enzyme activity was measured in the liver microsomal fraction in the presence of [(3)H]cortisone (10(-)(6) M) or [(3)H]cortisol (10(-)(6) M) and NADPH (reductase activity) or NADP(+) (dehydrogenase activity) respectively. 11beta-HSD1 reductase activity was significantly greater in the presence of cortisol. In summary, we found that, in sheep during late gestation, cortisol increased both 11beta-HSD1 and GR in the fetal liver, and these effects were accentuated in the absence of increased E(2).
Journal of Endocrinology 03/2003; 176(2):175-84. · 3.55 Impact Factor
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ABSTRACT: Prostaglandins (PGs) act as potent uterotonins at the time of labor. Prostaglandin E synthase (PGES) is responsible for the formation of PGE(2), a uterotonin. PGI(2) is synthesized by the prostaglandin I synthase enzyme (PGIS) and contributes to relaxation in the lower uterine segment. We examined the expression of membrane-bound PGES and PGIS in myometrium from pregnant women during preterm and term labor. Tissues were collected from the lower uterine segment from preterm no labor, preterm labor, term no labor, and term labor patients and used for immunohistochemistry and Western blot analysis using specific antibodies. Immunoreactive (ir-) PGES and PGIS proteins were localized to the cytoplasm of myocytes of the myometrium and vascular smooth muscle cells. Ir-PGES was also detected in vascular endothelial cells. Western blot analyses revealed a predominant protein band of 180 kDa, and a second 16-kDa band for ir-PGES and 56-kDa band for ir-PGIS. There was no significant change in ir-PGES protein (180 or 16 kDa) or mRNA levels with preterm or term labor or gestational age. There was a significant decrease in PGIS mRNA and protein with advancing gestational age. We conclude that the gestational age decrease in the inhibitory PGIS is consistent with lessening of its influence in myometrium at the time of labor. The lack of change in PGES indicates that alterations at other points along the pathway of arachidonic acid metabolism may be of greater importance in affecting local changes in PGE(2).
Journal of Clinical Endocrinology & Metabolism 12/2002; 87(11):5274-82. · 6.50 Impact Factor
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ABSTRACT: Preeclampsia (PE) is a major cause of maternal and perinatal morbidity and mortality. The genesis of PE is related to deficient trophoblast invasion of maternal spiral arteries, which might result in a reduction of placental (PL) oxygen (O(2)). An absence of increased O(2) that normally occurs around the 10-12th wk of gestation results in aberrant expression of genes that might contribute to the pathophysiology of PE. We examined the expression and regulation of PL 11 beta-hydroxysteroid dehydrogenase 2 (11 beta-HSD) in normal pregnancies and in PE. Two types of 11 beta-HSD exist in the placenta, 11 beta-HSD1 and 11 beta-HSD2. 11 beta-HSD2 is thought to protect the fetus from cortisol excess. In PE, both the expression and activity of PL 11 beta-HSD2 were reduced significantly compared with those in age-matched controls. As PE is associated with a reduction of PL O(2), we next investigated whether in normal pregnancy 11 beta-HSD2 expression changes at the time of the increase in O(2). 11 beta-HSD2 was detected as early as 5 wk, with expression limited to the syncytiotrophoblast (ST). At 10-12 wk, this expression increased and was also found in the cytotrophoblast and extravillous trophoblast. These results were substantiated by Western blot. The ability of O(2) to regulate 11 beta-HSD2 was determined both in cultures of villous explant from early gestation and in term trophoblast cells after incubation under 3% or 20% O(2). Villous explants cultured under 20% O(2) showed higher enzyme activity and expression compared with 3% O(2). Term trophoblast cells also exhibited higher enzyme activity at 20% vs. 3% O(2). No change in 11 beta-HSD1 expression was observed in early pregnancy or in PE. This is the first report to suggest that 11 beta-HSD2 is O(2) dependent in first and third trimester placenta during human gestation.
Journal of Clinical Endocrinology & Metabolism 11/2002; 87(10):4797-805. · 6.50 Impact Factor
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ABSTRACT: A general characteristic of fetal endocrine maturation across different species is the enhanced activity of the fetal hypothalamic-pituitary-adrenal (HPA) axis during late gestation. Precocious activation of this axis may occur when the fetus is exposed to an adverse intra-uterine environment, such as hypoxemia. HPA development is associated with increased levels of ACTH(1-39) and adrenal corticosteroids (cortisol in sheep and human) in the fetal circulation, and increased expression of mRNA encoding corticotrophin releasing hormone (CRH) in the hypothalamus, proopiomelanocortin (POMC) in the pituitary, and key steroidogenic enzymes in the fetal adrenal. At term, increased levels of cortisol act on the placenta/trophoblast derived cells to increase expression of prostaglandin synthase Type II (PGHS-II). In human gestation, cortisol also decreases expression of 15-hydroxyprostaglandin dehydrogenase (PGDH) in chorionic trophoblast cells. Increased synthesis and decreased metabolism of prostaglandin (PG) results, during late gestation, in enhanced output of primary PG, which in turn increases the activity of 11 beta-hydroxysteroid dehydrogenase (11 beta HSD) in the human fetal membranes. Increased chorionic 11 beta HSD-1 results in increased local generation of cortisol from cortisone, with further paracrine/autocrine stimulation of PG output. Increased fetal cortisol contributes to the maturation of organ systems required for postnatal extra-uterine survival. However, excessive levels of feto-placental glucocorticoid, derived from maternal administration of synthetic corticosteroids or sustained endogenous fetal cortisol production, results in intrauterine growth restriction. Fetal sheep, exposed to maternal betamethasone in late gestation, develop insulin resistance and exaggerated adrenal responses to HPA stimulation by 6-12 months postnatal life. Thus, the level of fetal HPA activity is crucial not only for determining gestation length, but may also predict pathophysiologic adjustments in later life.
Molecular and Cellular Endocrinology 01/2002; 185(1-2):135-44. · 4.19 Impact Factor
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ABSTRACT: In human pregnancy, cortisol and PGs are involved in the onset of labor and play an important role in the mechanisms leading to parturition. Recent studies have shown that at term, cortisol increases PG synthesis and decreases PG metabolism in chorion trophoblast (CT) cells. In CT, 11 beta-hydroxysteroid oxidase type 1 (11 beta-HSD1) converts biologically inactive cortisone to cortisol to regulate cortisol availability. In the present study, we have investigated whether 11 beta-HSD1 activity could be influenced by PGs. We have shown that in CT, PGF2alpha rapidly increased 11 beta-HSD1 reductase activity in a dose-dependent manner via the PGF2alpha receptor, localized in the fetal membranes. PGF2alpha stimulated 11 beta-HSD1 activity through increased intracellular calcium mobilization, activation of PKC, and the phosphorylation of the 11 beta-HSD enzyme. We propose that within CT there is a novel feed forward loop by which PGF2alpha acts to promote cortisol production from cortisone through increases in 11beta-HSD1, and this in turn leads to further net PG output for the onset of labor and birth.
Journal of Clinical Endocrinology & Metabolism 12/2001; 86(11):5585-92. · 6.50 Impact Factor
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ABSTRACT: Increased uterine contractility at term and preterm results from activation and then stimulation of the myometrium. Activation can be provoked by mechanical stretch of the uterus and by an endocrine pathway resulting from increased activity of the fetal hypothalamic-pituitary-adrenal (HPA) axis. In fetal sheep, increased cortisol output during pregnancy regulates prostaglandin H synthase type 2 (PGHS2) expression in the placenta in an estrogen-independent manner, resulting in increased levels of PGE2 in the fetal circulation. Later increases in maternal uterine expresssion of PGHS2 require elevations of estrogen and lead to increased concentrations of PGF2alpha in the maternal circulation. Thus, regulation of PGHS2 at term is differentially controlled in fetal (trophoblast) and maternal (uterine epithelium) tissue. This difference may reflect expression of the glucocorticoid receptor (GR), but not estrogen receptor (ER), in placental trophoblast cells. In women, cortisol also contributes to increased PG production in fetal tissues through upregulation of PGHS2 (amnion and chorion) and downregulation of 15-OH PG dehydrogenase (chorion trophoblasts). The effect of cortisol on chorion expression of PGDH reverses a tonic stimulatory effect of progesterone, potentially through a paracrine or autocrine action. We have interpreted this interaction as a reflection of "progesterone withdrawal" in the primate, in relation to birth. Other agents, such as proinflammatory cytokines, similarly upregulate PGHS2 and decrease expression of PGDH, indicating the presence of several mechanisms by which labor at term or preterm may be initiated. These different mechanisms need to be considered in the development of strategies for the detection and management of the patient in preterm labor.
Annals of the New York Academy of Sciences 10/2001; 943:225-34. · 3.15 Impact Factor
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ABSTRACT: Birth in many animal species and in humans is associated with activation of hypothalamic-pituitary-adrenal function in the fetus and the increased influence of glucocorticoids on trophoblast cells of the placenta and fetal membranes. We suggest that in ovine pregnancy glucocorticoids directly increase fetal placental prostaglandin production, and indirectly increase prostaglandin production by maternal uterine tissues through the stimulation of placental estradiol synthesis. The events of ovine parturition are compared with those of human parturition. In the latter, we suggest similar direct effects of glucocorticoids on prostaglandin synthesis and metabolism in fetal membranes and similar indirect effects mediated by glucocorticoid-stimulated increases in intrauterine corticotropin-releasing hormone expression.
Biology of Reproduction 05/2001; 64(4):1019-32. · 4.01 Impact Factor
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ABSTRACT: Birth in most animal species is triggered by the fetus through activation of the fetal hypothalamic-pituitary-adrenal (HPA) axis. Preterm birth, may be associated with precocious activation of fetal HPA function, reflecting the fetal response to an adverse intrauterine environment. There is a progressive and concurrent increase of ACTH1-39 and cortisol (F) in the circulation of fetal sheep during the last 15-20 days of pregnancy (term, day 145-150) associated with increased expression of hypothalamic CRH pituitary POMC and adrenal ACTH receptor and steroidogenic enzymes, particularly P450 C17. Similar changes occur with fetal hypoxemia. Negative feedback is ameliorated by decreased pituitary and hypothalamic glucocorticoid receptor, increased CBG, and altered fetal pituitary 11B-hydroxysteroid dehydrogenase type 1. Repeated fetal hypoxemia, diminishes the fetal-pituitary ACTH response, but increases fetal adrenal responsiveness. Fetuses exposed to maternal glucocorticoid in late gestation are growth restricted with altered postnatal HPA responsiveness and glycemic responses that reproduce the insulin resistance of type 2 diabetes. We conclude that the level of fetal HPA activity is crucial not only for determining gestation length, but also predicts pathophysiologic adjustment in later life.
Endocrine Research 12/2000; 26(4):489-504. · 0.97 Impact Factor
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ABSTRACT: Arginine vasopressin (AVP) and corticosteroid hormones are involved in sodium reabsorption regulation in the renal collecting duct. Synergy between AVP and aldosterone has been well documented, although its mechanism remains unclear. Both aldosterone and glucocorticoid hormones bind to the mineralocorticoid receptor (MR), and mineralocorticoid selectivity depends on the MR-protecting enzyme 11 beta hydroxysteroid deshydrogenase (11-HSD), which metabolizes glucocorticoids into derivatives with low affinity for MR. We have investigated whether the activity of 11-HSD could be influenced by AVP and corticosteroid hormones. This study shows that in isolated rat renal collecting ducts, AVP increases 11-HSD catalytic activity. This effect is maximal at 10(-8) M AVP (a concentration clearly above the normal physiological range of AVP concentrations) and involves the V2 receptor pathway, while activation of protein kinase C or changes in intracellular calcium are ineffective. The stimulatory effect of AVP on 11-HSD is largely reduced after adrenalectomy, and is selectively restored by infusion of aldosterone, not glucocorticoids. We conclude that this synergy between AVP and aldosterone in controlling the activity of 11-HSD is likely to play a pivotal role in resetting mineralocorticoid selectivity, and hence sodium reabsorption capacities of the renal collecting duct.
Journal of Clinical Investigation 12/1997; 100(10):2437-42. · 15.39 Impact Factor
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ABSTRACT: It has been suggested that aldosterone exerts direct effects on heart functioning, in particular by inducing cardiac fibrosis. We examined human heart tissue for the expression of aldosterone receptors (mineralocorticoid receptors, MRs) and of the MR-protecting enzyme, 11 beta hydroxysteroid dehydrogenase (11 beta HSD). In situ hybridization using cRNA probes specific for human MRs revealed the presence of mRNA encoding for MRs in cardiomyocytes. Immunohistochemistry with specific antibodies against the MR exhibited the expression of MR protein in cardiomyocytes. In contrast, intramyocardial small blood vessels showed no evidence of immunolabelling. A distinct 11 beta HSD activity, which was nicotinamide-adenine dinucleotide dependent, was also demonstrated in human cardiac tissue. These results illustrate that all the components required for a specific aldosterone effect are present in the human heart.
European Heart Journal 01/1996; 16 Suppl N:92-7. · 10.48 Impact Factor
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ABSTRACT: It has been proposed that aldosterone exerts direct effects on heart function, most notably on the development of myocardial fibrosis during ventricular hypertrophy in rat. Initial events in aldosterone action entail its binding to mineralocorticoid receptor (MR). Because MR displays similar affinities for aldosterone and glucocorticoids, the in vivo aldosterone selectivity of MR requires the presence of an enzyme, 11 beta-hydroxysteroid dehydrogenase (11-HSD), which metabolizes glucocorticoids into inactive derivatives. Although evidence exists for the presence of MR in rodent heart, no data are available for humans; moreover, the existence of cardiac 11-HSD is controversial.
The heart samples used originated from tissue removed during cardiac surgery in nontransplant patients or from endocavitary biopsies done for the follow-up of heart transplantation. The expression of MR was examined at the mRNA and protein level by in situ hybridization with cRNA probes specific for human MR mRNA and by immunodetection with two specific anti-MR antibodies. 11-HSD catalytic activity was determined by measurement of the metabolic rate of tritiated corticosteroids by cardiac samples. In nontransplanted hearts, an in situ hybridization signal equivalent to that found in the whole kidney was present on cardiomyocytes. Specific immunolabeling of cardiomyocytes with anti-MR antibodies demonstrated the presence of the MR protein. Cardiac 11-HSD activity was detected (243 +/- 26 fmol.30 min-1.mg protein-1) and was dependent on the cofactor NAD, not NADP, suggesting that it corresponds to the form of the enzyme specifically responsible for MR protection. In transplanted hearts that presented severe alterations, MR immunodetection was weaker and irregular, with no specific hybridization signal.
Our results demonstrate that MR is coexpressed with 11-HSD in human heart, which thus possesses the cellular machinery required for direct aldosterone action.
Circulation 08/1995; 92(2):175-82. · 14.74 Impact Factor
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ABSTRACT: Enzymatic properties of the enzyme 11 beta-hydroxysteroid dehydrogenase (11-HSD), which confers mineralocorticoid selectivity, have been explored in the aldosterone-sensitive collecting duct (CCD) and the aldosterone-insensitive Pars Recta (PR) of the rat kidney. After incubation of freshly isolated tubular segments with [3H]corticosterone (3H-B) or [3H]dehydrocorticosterone (3H-A), the rate of transformation of 3H-B into 3H-A (dehydrogenase activity), or the reverse reaction (reductase activity) were measured by HPLC, Vmax for dehydrogenase activity was found to be 8- to 10-fold higher in CCD than PR. The enzyme functions over a very wide range (0.1-5000 nM) of corticosterone concentration. In CCD, enzyme kinetics suggest either the presence of two 11-HSD forms, differing by their affinity for corticosterone, or complex kinetics. Addition of NAD or NADP to permeabilized tubules revealed that dehydrogenase activity is NAD-dependent in CCD and NADP-dependent in PR. Cofactor addition was ineffective in intact tubules. CCD exhibited an exclusive dehydrogenase activity, whereas in PR dehydrogenase and reductase activity were found. No regulation of dehydrogenase activity could be evidenced in adrenalectomized rats receiving or not aldosterone, corticosterone or dexamethasone, for 2 h, 3 days or 4 days. We conclude that 11-HSD in the CCD and PR differs by its Vmax and cofactor dependence. Corticosteroid hormones do not influence 11-HSD activity.
Biochimica et Biophysica Acta 05/1995; 1243(3):461-8. · 4.66 Impact Factor
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ABSTRACT: The enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta-OHSD) plays a major role in the protection of the mineralocorticoid receptor (MR). This cellular mechanism of aldosterone selectivity relies on the coexpression of MR and 11 beta-OHSD in the same cells. Localization of renal 11 beta-OHSD along the nephron is reviewed; comparison of data contained in different species is made; and original data is presented to show that the catalytic activity of the enzyme in tubules from human kidney is the highest in the mineralocorticoid-sensitive distal nephron.
Steroids 03/1994; 59(2):100-4. · 2.83 Impact Factor
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ABSTRACT: Copper is an essential trace element for successful pregnancy. However, the mechanisms by which copper is transported from maternal circulation to the fetus have not been clearly elucidated. Two proteins, cellular prion (PrP(C)) and COMMD1, are known to be responsible for prion diseases and canine copper toxicosis, respectively, and are thought to play a role in copper homeostasis. However, their placental expression and localization throughout human gestation are still unknown. In this study, we used quantitative RT-PCR, western blotting and immunohistochemistry to investigate in detail the expression and localization of PrP(C) and COMMD1 proteins in human placenta throughout pregnancy. Our results show that both proteins are expressed in human placenta. PrP(C) showed the highest mRNA and protein expression levels during the first trimester of pregnancy. PrP(C) and COMMD1 proteins are similarly localized within the placental villi. Both proteins are present in the syncytiotrophoblast, the cytotrophoblast, vascular endothelial cells and Hofbauer cells. These data offer some insights into possible roles for PrP(C) and COMMD1 within the placenta.
Placenta 28(8-9):907-11. · 3.69 Impact Factor
