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The Journal of Clinical Endocrinology & Metabolism Vol. 85, No. 3 1306-1309
Copyright © 2000 by The Endocrine Society

Original Studies

11ß-Hydroxysteroid Dehydrogenase Type II and Mineralocorticoid Receptor in Human Placenta1

Gen Hirasawa2, Junji Takeyama, Hironobu Sasano, Kouhei Fukushima, Takashi Suzuki, Yasunari Muramatu, Andrew D. Darnel, Chika Kaneko, Nobuo Hiwatashi, Takayoshi Toyota, Hiroshi Nagura and Zygmunt S. Krozowski

Departments of Pathology (G.H., J.T., H.S., T.S., Y.M., A.D.D., C.K., H.N.), Internal Medicine (G.H., N.H., T.T.), and Surgery (K.F.), Tohoku University School of Medicine, Sendai, Miyagi 980-8575, Japan; and Laboratory of Molecular Hypertension, Baker Medical Research Institute (Z.S.K.), Melbourne 8008, Australia

Address correspondence and requests for reprints to: Junji Takeyama, M.D., Department of Pathology, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan. E-mail: j-takeyama{at}patholo2.med.tohoku.ac.jp


   Abstract
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 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
In mineralocorticoid target organs, 11ß-hydroxysteroid dehydrogenase type II (11ß-HSD2) confers specificity on the mineralocorticoid receptor (MR) by converting biologically active glucocorticoids to inactive metabolites. Placental 11ß-HSD2 is also thought to protect the fetus from high levels of circulating maternal glucocorticoid. In this study, we examined the immunoreactivity of 11ß-HSD2 and MR in human placenta from 5 weeks gestation to full term using immunohistochemistry, 11ß-HSD2 messenger RNA (mRNA) expression using Northern blot analysis, and MR mRNA expression using RT-PCR analysis. Marked 11ß-HSD2 immunoreactivity was detected in placental syncytiotrophoblasts at all gestational stages. MR immunoreactivity was moderately detected in syncytiotrophoblasts, some cytotrophoblasts, and interstitial cells of the villous core. Marked mRNA expression of 11ß-HSD2 was detected in placenta by Northern analysis. RT-PCR analysis of MR in placental tissues showed an amplified product consistent in length with the primers selected. These results suggest that placental 11ß-HSD2 is involved in not only regulating the passage of maternal active glucocorticoids into the fetal circulation but also in regulation of maternal-fetal electrolyte and water transport in the placenta, as in other mineralocorticoid target organs.


   Introduction
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 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
IT IS NOW well established that 11ß-hydroxysteroid dehydrogenase type II (11ß-HSD2) confers specificity on the nonselective mineralocorticoid receptor (MR) (1) by converting biologically active glucocorticoids to inactive metabolites, thereby allowing the approximately 1000-fold lower circulating levels of aldosterone to bind to MR (2, 3). Aldosterone binds intracellular MR, which in turn modulates the transcription of genes regulating water and electrolyte transport (4, 5). Recently, we reported colocalization of 11ß-HSD2 and MR not only in classical human mineralocorticoid target tissues such as colon, kidney, and exocrine cells of salivary glands, but also in novel target tissues such as respiratory tract, by immunohistochemistry of mirror image serial tissue sections (6). Placental syncytiotrophoblasts are considered nonmineralocorticoid target cells, and placental 11ß-HSD2 is thought to be primarily involved in protecting the fetus from high circulating maternal glucocorticoids (7, 8, 9). However, Stulc (10) recently reviewed placental transport and suggested that this tissue has properties more closely resembling mineralocorticoid target tissues than diffusional transport organs, such as capillaries. In addition, DOC-SO4, which is present in pregnant women at 100 times the levels in nonpregnant women, is produced in the placenta and is ideally placed to exert paracrine effects on removal of only a fraction of the sulphate groups (11). This study, thus, examines in parallel the expression of both MR and 11ß-HSD2 in human placenta using immunohistochemistry, Northern blotting and RT-PCR analysis.


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Tissue collection and preparation

Human placental tissues from 5–20 weeks gestation (n = 7) were obtained after elective termination in noncomplicated normal pregnant women at Tohoku University Hospital and Nagaike Maternal Clinic (Sendai, Japan), and those from 30–40 gestational weeks (n = 4) were obtained at normal spontaneous vaginal delivery at Tohoku University Hospital (Table 1Go). The study protocol was approved by the Ethics Committee of Tohoku University School of Medicine. All specimens for immunohistochemical examination were fixed in 10% neutral formalin for 18 h at room temperature and embedded in paraffin. These specimens were subsequently sectioned at 3 µm and mounted on silane-coated glass slides (Matsunami Co. Ltd., Tokyo, Japan). There were no significant abnormalities on histological examination of these specimens. Fresh frozen specimens of placenta obtained from elective termination at 13 and 20 gestational weeks of noncomplicated normal pregnancy and normal spontaneous vaginal delivery at 30 and 40 weeks were obtained for RNA analysis. Fresh frozen kidney tissue from a radical nephrectomy was used as a positive control in RT-PCR analysis. Subsequent histological examination of these specimens did not reveal any significant abnormalities. Total RNA was extracted by homogenizing tissue specimens in guanidinium thiocyanate, followed by ultracentrifugation in cesium chloride, as described previously (12), and quantified spectrophotometrically at 260 nm.


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  		Table 1. Immunoreactivity of MR and 11ß HSD2 in the human placenta

 
Primary antibody

The generation and characterization of the primary antibodies for 11ß-HSD2 (HUH23) and MR (MINREC4) have been described previously (13, 14). Briefly, HUH23 is an immunopurified polyclonal antibody raised in rabbits against a synthetic peptide corresponding to the last 16 amino acid residues of human 11ß-HSD2. The polyclonal antibody MINREC4 was raised in rabbits against a synthetic fusion protein corresponding to 167 amino acids of the N-terminal region of the human renal MR. Use of these antibodies in immunohistochemistry has been reported previously (6, 15); MINREC4 does not cross-react with glucocorticoid receptors (GR) (16, 17). van Steensel et al. (16) reported that GR and MR were present in separate nuclear compartments in rat hippocampal neurons using MINREC4 as the primary antibody in immunohistochemistry. In addition, immunohistochemical analysis of MR in human kidney using MINREC4 demonstrated immunoreactivity in distal tubules and collecting ducts, but not in proximal tubules where GR is located (15).

Immunohistochemistry

Immunohistochemical analysis was performed by the streptavidin-biotin amplification method using a Histofine Kit (Nichirei, Tokyo, Japan) and has been described in detail previously (6, 15). The HUH23 antibody was used at a final concentration of 5 µg/mL and MINREC4 was used at a dilution of 1:600. The antigen-antibody complex was visualized with 3.3'-diaminobenzidine (DAB) solution [1 mM DAB, 50 mM Tris-HCl buffer (pH 7.6), and 0.006% H2O2], and counterstained with hematoxylin. Adult human kidney tissues were used as positive controls for 11ß-HSD2 and MR. For negative controls, preimmune rabbit serum was used instead of primary antibodies, and no specific immunoreactivity was detected in these sections.

For absorption test of MR immunoreactivity, an antibody-antigen mixture containing equal volumes of the optimally diluted antiserum to MR and MR peptide solution was incubated for 18 h at 4 C. After centrifugation, the resultant supernatants were used as preabsorbed antibody.

Northern blot analysis for 11ß-HSD2

Total RNA (20 µg) from normal human placenta was electrophoresed in 1% agarose-2% formaldehyde gels in MOPS buffer. RNA was transferred onto Hybonda-N+ positively charged nylon membranes (Amersham, Buckinghashire, UK) and UV cross-linked. Full-length (1885 bp) human 11ß-HSD2 cDNA (8) and a 540-bp fragment (113 to 652) from human ß-actin complementary DNA (19) were used as probes. Each fragment was labeled with digoxigenin (DIG)-labeled dUTP using the DIG Nucleic Acid Detection Kit (Boehringer Mannheim, Mannheim, Germany) according to the manufacturer’s instructions. Membrane was prehybridized for 4 h at 42 C in hybridization buffer (50% deionized formamide, 5x SSC, 0.1% N-Lauroylsarcosine, 0.02% SDS, and 2% blocking reagent supplied), followed by hybridization with DIG-labeled probe for 16 h at 42 C. The membrane was then washed twice in 2 x SSC and 0.1% SDS at room temperature for 5 min, and twice in 0.1 x SSC and 0.1% SDS at 65 C for 30 min. The hybridized probes were immunodetected with anti-DIG, Fab fragments conjugated to alkaline phosphatase (Boehringer Mannheim) and are then visualized with the chemiluminescence substrate CDP-Star (Tropix Inc., Bedford, MA) using DIG Luminescent Detection Kit (Boehringer Mannheim). After washing, the membrane was incubated with 1% blocking buffer supplied for 30 min and then anti-DIG Fab fragments, conjugated with alkaline phosphatase for 30 min, followed by an incubation in a solution containing CDP Star at a concentration of 1:500 for 5 min. The blots were then visualized by Lumino-imazing analyzer LAS-1000 (Fuji Photofilm Co., Ltd., Tokyo, Japan).

RT-PCR for human MR

Human MR mRNA was detected by RT-PCR using synthesized sense (1237–1258 bp) and antisense (1811–1790 bp) primers according to the reported sequence (18). Complementary DNA was prepared from total RNA (1 µg) extracted from human placenta and kidney in 20 µL reverse transcription buffer containing 50 mM Tris-HCl (pH 8.3), 55 mM KCl, 3 mM MgCl2, 0.02 M DTT, 0.5 mM dNTP, 62.5 mg/mL oligo (dT) 12–18, and 100 U RNase H-reverse transcriptase (Life Technologies Inc., Gaithersburg, MD) at 42 C for 60 min. The reaction mixture was subsequently inactivated for 10 min at 90 C and diluted 4-fold with Tris-EDTA buffer. Diluted RT reaction mixture (2 µL) was combined with 1x PCR buffer supplied, 1.5 mM MgCl2, 0.1 mM dNTP and 1.25 U Taq polymerase (Amersham), up to a total volume of 25 µL. This volume was overlaid with mineral oil and then incubated in a RoboCycler (Stratagene, La Jolla, CA). The amplification profile consisted of denaturation at 95 C for 1 min, annealing at 54 C for 1.5 min, and extension at 72 C for 2 min with 35 cycles. The sequence of the amplified product was confirmed using Cy5 AutoCycle Sequencing Kit (Pharmacia Biotech, Tokyo, Japan). The human glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA was also amplified as an internal standard using the primer set (sense, 586–605 bp; antisense, 1018–1037) (20). The resulting products were then gel electrophoresed and visualized by ethidium bromide staining.


   Results
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 Abstract
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 Materials and Methods
 Results
Discussion
 References
 
Immunohistochemistry

Results of immunohistochemistry of 11ß-HSD2 and MR in normal human placental tissues are summarized in Table 1Go. Immunoreactivity for 11ß-HSD2 was markedly detected in the human placental syncytiotrophoblasts facing the maternal circulation throughout all gestational stages. Vascular endothelial cells of placental villi were not stained by 11ß-HSD2 (Fig. 1Go, A, C, and E). MR immunoreactivity was moderately detected in syncytiotrophoblasts, some cytotrophoblasts, and interstitial cells of the villous core (Fig. 1Go, B, D, and F). The immunoreactivity of MR was abolished by the MR antiserum preabsorbed with the antigen (data not shown).



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  		Figure 1. Immunohistochemical staining of 11ß-HSD2 at 6 (A), 20 (C), and 40 (E) weeks gestation and of MR at 6 (B), 20 (D), and 40 (F) weeks gestation in human placenta. Immunopositive cells appear brown as a result of diaminobenzidine colorimetric reaction. Marled immunoreactivity for 11ß-HSD2 was detected in syncytiotrophoblasts of human placenta throughout gestation. Moderate immunoreactivity of MR was detected in syncytiotrophoblasts, some cytotrophoblasts, and interstitial cells of the villous core. Hematoxylin was used as the nuclear stain. Magnification, x200 (A–D), x400 (E and F).

 
Northern blot analysis for 11ß-HSD2

Expression of the 1.9-kb messenger RNA (mRNA) for 11ß-HSD2 was detected in all human placental tissues examined (Fig. 2Go). ß-actin, used as an internal standard, was also detected in all tissues examined (Fig. 2Go).



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  		Figure 2. Northern blot analysis of 11ß-HSD2 mRNA in human placenta. The size of the message is 1.9 kb, consistent with the full-length cDNA. Bottom panel shows corresponding ß-actin bands as controls.

 
RT-PCR for human MR

RT-PCR yielded bands consistent with the detection of MR at 574 bp. This band was present in placenta at 13, 20, 30, and 40 weeks of gestation, as well as in human kidney (Fig. 3Go). The GAPDH control achieved equal band intensity throughout (Fig. 3Go).



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  		Figure 3. RT-PCR analysis of human MR and GAPDH. Lane MW was a 100-bp molecular marker. Specific bands consistent with MR (574 bp) were clearly detectable in human placenta at 13, 20, 30, and 40 weeks gestation, and in human kidney. The control GAPDH RT-PCR product (451 bp) is also shown for human placenta and kidney.

 

   Discussion
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In the present study, we detected marked expression of 11ß-HSD2 mRNA in human placenta and intense immunoreactivity for 11ß-HSD2 in human placental syncytiotrophoblasts, which are consistent with previous reports (13, 21). Treatment of pregnant rats with dexamethasone, a synthetic glucocorticoid only partially inactivated by 11ß-HSD2 (22), reduced average birth weight by 14% and caused persistent hypertension in the adult offspring (23). Recently, placental 11ß-HSD2 activity has been shown to rise during the course of pregnancy in human and to be significantly lower in births complicated by intrauterine growth retardation (24). These observations are consistent with the important role played by 11ß-HSD2 in protecting the fetus from high levels of maternal glucocorticoids (8, 9, 25).

On the other hand, glucocorticoids play an important role in fetal development, especially the induction of surfactant synthesis (26) and fetal lung maturation (27). All infant rats born as a result of matings between homozygous CRH-deficient mice die within the first 12 h, but there is no significant increase in mortality of CRH-deficient animals from heterozygote matings, presumably because the heterozygous mother provides sufficient glucocorticoid to mature the respiratory system and rescue the homozygous offspring (28).

The conversion of cortisone to cortisol in homogenized human placental tissue increases toward term (29). Recently, Sun et al. (8) reported that the 11ß-HSD type 1 enzyme (11ß-HSD1), which converts cortisone to cortisol, was immunohistochemically detected in extravillous cytotrophoblasts and vascular endothelium of human placenta, and that immunoreactivity increased with gestational age. Therefore, placental 11ß-HSD may play important roles not only in excluding maternal glucocorticoids from the fetus, but also in modulating glucocorticoid access to the fetus during development. The capacity for such developmental change would be greatly facilitated by the coexpression of 11ß-HSD1 and 11ß-HSD2 in the placenta (8, 9, 30).

There has been no definitive evidence of mineralocorticoid activity in placental tissue since 11ß-HSD2 activity in placenta was first reported in 1960 (31). Binding and in situ hybridization studies were unable to detect MR in placenta (7, 9). Nevertheless, we could detect MR mRNA expression in human placenta by using the more sensitive RT-PCR techniques. Furthermore, MR immunoreactivity, although less intense than 11ß-HSD2 immunoreactivity, was also detected in syncytiotrophoblasts and some cytotrophoblasts. Given the high levels of 11ß-HSD2, these results suggest that mineralocorticoids may act on the human placenta to stimulate feto-maternal water and electrolyte transport. However, it awaits further investigations, including aldosterone binding studies or autoradiograms, for confirmation of the presence of MR in human placental tissues. Recently, Patel et al. (32) reported that cortisol inhibits placental 15-hydroxyprosta-glandin dehydrogenase with an IC50 of 0.1 nM, and that this effect is enhanced in the presence of carbenoxolone. Such a high affinity is consistent with action through the MR with 11ß-HSD2, allowing aldosterone to occupy these sites in vivo. Therefore, the expression of MR suggest that the biological roles of 11ß-HSD2 in the human placenta is not only the protection of the fetus from the high circulating levels of maternal glucocorticoids, but also the regulation of electrolyte and water transport between the mother and fetus. Further investigations including the study of possible effects of inhibitors of placental 11ß-HSD2, such as carbenoxolone on possible electrolytes transport across the placenta, are required for clarification of the biological roles of placental MR and 11ß-HSD2.


   Footnotes
 
1 This work was supported by the grant-in-aid for Cancer Research 7-1 from the Ministry of Health and Welfare, Japan; a grant-in-aid for scientific research area on priority area (A-11137301) from The Ministry of Education, Science and Culture, Japan; a grant-in-aid for Scientific Research (B-11470047) from Japan Society for the Promotion of Science; and a grant from The Naitou Foundation and Suzukenn Memorial Foundation. Back

2 Present address: Department of Radiology, University of Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75235. Back

Received February 9, 1999.

Revised November 4, 1999.

Accepted November 19, 1999.


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 Materials and Methods
 Results
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