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

Departments of Pediatrics (E.S., M.G., H.G.D., W.R., J.D.) and Obstetrics and Gynecology (W.F.), University of Erlangen-Nuremberg, 91054 Erlangen; and Department of Obstetrics and Gynecology, University of Giessen (M.K.), 35385 Giessen, Germany

Address all correspondence and requests for reprints to: Jörg Dötsch, M.D., Klinik für Kinder und Jugendliche, Friedrich-Alexander-Universität Erlangen-Nürnberg, Loschgestrasse 15, 91054 Erlangen, Germany. E-mail: joergwdoetsch{at}yahoo.com

	Abstract

Top Abstract Introduction Materials and Methods Results Discussion References

 
Cortisol reduces the activity of the PG-inactivating enzyme 15-hydroxyprostaglandin dehydrogenase (PGDH) in human placental cells. The objective was to investigate a possible relation between 11ß-hydroxysteroid dehydrogenase type 2 (11ß-HSD2), converting cortisol to cortisone, and PGDH gene expression in the placenta of patients with preeclampsia.

In placental tissue taken from 20 healthy women with normal pregnancy, 20 premature babies born after labor before term, and 18 neonates after preeclamptic pregnancy, 11ß-HSD2 and PGDH messenger RNA (mRNA) expression was determined using quantitative TaqMan real-time PCR and quantitative competitive PCR. When comparing matched pairs, there were 3-fold lower 11ß-HSD2/glyceraldehyde-3-phosphate dehydrogenase (11ß-HSD2/GAPDH) mRNA levels in placentas of patients with preeclampsia than in controls [0.18 ± 0.04 relative units (RU) and 0.61 ± 0.10 RU, P = 0.0003]. We also found a 2-fold reduction in placental PGDH/GAPDH mRNA concentrations (0.28 ± 0.15 RU and 0.50 ± 0.18 RU, P = 0.0003). PGDH and 11ß-HSD2 mRNA levels correlated significantly (r = 0.66, P < 0.0001). In term placenta, 11ß-HSD2/GAPDH, but not PGDH, showed a significant correlation to birth weight (r = 0.43, P = 0.01) and to placental weight (r = 0.47, P = 0.01). Results could be confirmed by competitive PCR.

We conclude that, in preeclampsia, 11ß-HSD2 mRNA expression is reduced, leading to the known decrease of 11ß-HSD2 activity. By means of an autocrine or paracrine mechanism, the diminished conversion of placental cortisol may lead to reduced PGDH mRNA expression as found in the present study.

	Introduction

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PREECLAMPSIA, a multiorgan disease recognized, in most cases, by hypertension and proteinuria, occurs in about 3–5% of pregnancies in nulliparous women (multiparae, 0.5%). It remains a leading cause of morbidity and mortality in mothers as well as in infants. Among its complications, intrauterine growth restriction and premature birth play an important part (1, 2). In placental tissue of patients with preeclampsia, decreased 11ß-hydroxysteroid dehydrogenase type 2 (11ß-HSD2) activity is accompanied by an increase in venous cord blood cortisol levels and impaired fetal weight (3). Excess of glucocorticoid exposure during fetal life has been shown to affect fetal growth (4) and has been implicated in the development of hypertension in adult life (5). The mechanism of reduced 11ß-HSD2 enzyme activity has not been elucidated, probably because of difficulties with the measurement of 11ß-HSD2 enzyme activity in vitro (6). We therefore tested the hypothesis that messenger RNA (mRNA) expression of the 11ß-HSD2 gene is responsible for altered enzyme function.

In human placenta and fetal membranes, 11ß-HSD enzymes exist in two isoforms. The type 1 NADP⁺-dependent form is predominantly found in fetal membranes and acts primarily as an 11-oxoreductase (formation of cortisol from cortisone) (7). The type 2 NAD⁺-dependent form (11ß-HSD2), in contrast, is the major form expressed in the syncytiotrophoblast of the placenta and converts cortisol to mineralocorticoid inactive cortisone (8, 9). The two 11ß-HSD enzymes form a metabolic barrier in the placenta by regulating transplacental passage of glucocorticoids and protecting the fetus from increasing maternal glucocorticoid levels (10).

Patel et al. (11) have shown that cortisol inhibits PG dehydrogenase (PGDH) activity in a dose-dependent manner and significantly decreased PGDH mRNA levels in placental and chorion trophoblast cells.

PGDH is the main enzyme responsible for the metabolism of PG E₂ (PGE₂) and PGF₂. It exists in two isoforms. Type 1, the NAD⁺-dependent isoform is primarily responsible for the formation of 15-keto-prostaglandins in placenta and chorion. It is predominantly found in chorionic trophoblasts, but it is also localized in the syncytiotrophoblast and intermediate trophoblast of the placenta (12). PGDH prevents passage of PGs synthesized from amnion or chorion to the decidua and myometrium for most of pregnancy and thus minimizes myometrial contractility (12).

In the present study, we examined whether reduced gene expression of cortisol inactivating 11ß-HSD2 in the placenta of patients with preeclampsia leads to a down-regulation of PGDH mRNA expression. Therefore, 11ß-HSD2 and PGDH gene expression were measured using quantitative real- time PCR.

	Materials and Methods

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Patients

Placental tissue was obtained in collaboration with the Departments of Gynecology and Obstetrics at the Universities of Erlangen-Nuremberg and Giessen. The study was approved by the ethics committee. Placental tissue was obtained at the time of vaginal delivery or cesarean section from 3 different parts of the placenta after removal of amniotic membrane and maternal decidua. Placental tissue from 20 healthy women with normal pregnancy (age, 21–36 yr at 36–42 weeks of gestation) and from 17 patients with 20 premature infants born after labor before term (18–34 weeks of gestation; age, 15–41 yr), was compared with 18 placentas from 15 patients with preeclampsia (age, 22–39 yr at 28–42 weeks of gestation). Preeclampsia was diagnosed according to international criteria (1). Seven patients did not receive any antihypertensive drugs; 7 patients received dihydralazine; 1, presinol; and 2, both drugs. Patients’ characteristics are shown in Table 1.

Total RNA was extracted from the tissues using guanidine-thiocyanate acid phenol (RNAzol, WAK Chemie, Medical GmbH, Bad Homburg, Germany). Considering the fact that placenta has a heterogeneous nature, RNA was extracted from 2 separate parts and quantified twice from 12 placental samples of preeclampsia patients and 22 respective matched controls.

The RNA concentration was determined spectrophotometrically. One microgram of RNA was reversely transcribed in a vol of 20 µL at 39 C for 60 min (all chemicals were obtained from Roche Molecular Biochemicals, Mannheim, Germany).

TaqMan real-time PCR

The method has been described for the measurement of gene expression in placental tissue before (13, 14). This novel approach is based on the 5' exonuclease activity of the Taq polymerase. Briefly, within the amplicon defined by a gene-specific oligonucleotide primer pair, a oligonucleotide probe labeled with 2 fluorescent dyes is designed. As long as the probe is intact, the emission of a reporter dye (i.e. 6-carboxy-fluorescein, FAM) at the 5'-end is quenched by the second fluorescence dye (6-carboxy-tetramethyl-rhodamine, TAMRA) at the 3'-end. During the extension phase of the PCR, the Taq polymerase cleaves the probe, releasing the reporter dye. An automated photometric detector, combined with a special software (ABI Prism 7700 Sequence Detection System, Perkin-Elmer Corp., Foster City, CA) monitors the increasing reporter dye emission. The algorithm normalizes the signal to an internal reference (Rn) and calculates the threshold cycle number (C_T), when the Rn reaches 10 times the SD of the baseline. The C_T values of the probes are interpolated to an external reference curve constructed by plotting the relative or absolute amounts of a serial dilution of a known template vs. the corresponding C_T values.

Commercial reagents (TaqMan PCR Reagent Kit, Perkin-Elmer Corp.) and conditions according to the manufacturer’s protocol were employed. Then, 2.5 µL complementary DNA (RT mixture) and oligonucleotides with a final concentration of 300 nmol/L of primers and 200 nmol/L TaqMan hybridization probe were added to 25 µL reaction mix. The oligonucleotides of each target of interest were designed by the Primer Express software (Perkin-Elmer Corp.) using uniform selection parameters that allowed the application of the same cycle conditions confirmed by primer optimization. All of the primers and probes were purchased from Perkin-Elmer Corp. PE Applied Biosystems. The thermocycler parameters were 50 C for 2 min, 95 C for 10 min, followed by 40 cycle of 95 C for 15 sec and 60 C for 1 min. A serial dilution of known copy numbers of a PCR product served as reference, providing a relative quantification of the unknown samples.

11ß-HSD2 and PGDH gene expression was related to the housekeeping genes glyceraldehyde-3-phosphate dehydrogenase (GAPDH), ß- actin, and porphobilinogen deaminase (PBGD).

The following primers and TaqMan probes were used—GAPDH: forward 5'-CCCATGTTCGTCATGGGTGT-3', reverse 5'-TGGTCATGAGTCCTTCCACGATA-3', TaqMan probe 5'(FAM)-CTGCACCACCAACTGCTTAGCACCC-(TAMRA)3'; ß-actin: forward 5'-GCGAGAAGATGACCCAGGATC-3', reverse 5'-CCAGTGGTACGGCCAG- AGG-3', TaqMan probe 5'(FAM)-CCAGCCATGTACGTTGCTATCCAGGC-(TAMRA)3'; PBGD: forward 5'-TGTGCTGCACGATCCCG-3', reverse 5'-ACACTGCAGCCTCCTTCCAG-3', TaqMan probe 5'(FAM)-CTTCGCTGCATCGCTGAAAGGGC-(TAMRA)3'; 11ß-HSD2: forward 5'-CCGTATTGGAGTTGAACAGCC-3', reverse 5'-CAACTACTTCATTGTGGCCTGC-3', TaqMan probe 5'(FAM)-CTAGAGTTCACCAAGGCCCACACCACC-(TAMRA)3'; and PGDH: forward 5'-AAGCAAAATGGAGGTGAAGGC-3', reverse 5'-TGGCATTCA GTCTCACAC- CAC-3', TaqMan probe 5'(FAM)-CATCTTTAGCAG GACTCATGC- CCGTTG-(TAMRA)3'.

Competitive PCR

To validate the TaqMan real-time measurements in seven placental samples of preeclampsia patients and seven samples of gestational age-matched controls ,11ß-HSD2 and ß-actin were measured by competitive PCR as well.

PCR was carried out with 25 µL reaction mixture containing 1 µL RT mixture, 1 µL 5'and 3' primer each (20 pmol/µL), 0.5 µL deoxynucleotide triphosphates (1 mmol/L each), 2.5 µL 10x PCR-buffer, 0.6 U Taq DNA polymerase (all chemicals were obtained from Roche Molecular Biochemicals), 16.5 µL deionized water, and 2.5 µL competitive standard dilution. After denaturation at 94 C for 1 min, 30 PCR cycles were carried out: denaturation at 94 C for 15 sec, annealing at 68 C for 30 sec, and extension at 72 C for 1 min. A final extension of 7 min (72 C) concluded the PCR cycle.

A competitive reverse transcriptase-PCR assay for quantitation of 11ß-HSD2 mRNA was used. A truncated internal standard with a length of 525 bases was synthesized as described elsewhere (15) and used as a competitor for the specific human 11ß-HSD2 (length, 576 bases). Titration of the unknown sample was carried out with serial 1:2 dilutions of the truncated complementary DNA standard. Standard and sample PCR-products were size fractionated by agarose gel electrophoresis and visualized by ethidium bromide staining. At equal band intensity of PCR-template and truncated standard, the dilution of the competitive standard was recorded. The mRNA amount was related to ß-actin mRNA (length, 753 bp), which was similarly quantified with a truncated actin standard (length, 658 bp).

The following primers were used: ß-actin: forward 5-GGT GGG CAT GGG TCA GAA GGA TTC C-3, reverse 5-GGC GTA CAG GTC TTT GCG GAT GTC C-3, standard 5-GCG GAT GTC CTG CCT CAG GGC AGC GGA ACC-3; 11ß-HSD2: forward 5-CAG ATG GAC CTG ACC AAA CCA GGA G-3, reverse 5-CAT CTG TGA TGG CAT CTA CAA CTG GG-3, standard 5-CTA CAA CTG GGA ACT GCC CAT GCA AGT GCT CG-3.

Statistical analysis

All values are expressed as mean ± SEM. After testing for Gaussian distribution, parametric data were compared using Student’s t test. To test parametric data for correlation, linear regression was used. Data of mRNA expression were compared using matched pairs. A P-value of less than 0.05 was considered significant.

	Results

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When comparing matched pairs, there were significantly lower placental 11ß-HSD2/GAPDH mRNA levels in patients with preeclampsia than in controls (0.18 ± 0.04 RU and 0.61 ± 0.10 RU, respectively, P = 0.0003, Fig. 1). The same results could be obtained when normalizing 11ß-HSD2 gene expression to ß-actin (P < 0.0001) or PBGD (P < 0.0001).

View larger version (16K): [in this window] [in a new window]   Figure 1. 11ß-HSD2/GAPDH mRNA expression in placental tissue of patients with preeclampsia and in gestational age-matched normal controls. Values are expressed as mean ± SEM. There is a significant difference between the two groups (P = 0.0003). Similar results were seen for normalization to ß-actin and PBGD gene expression.

View larger version (16K): [in this window] [in a new window]   Figure 2. PGDH/GAPDH mRNA expression in placentas of patients with preeclampsia and in gestational age-matched normal controls. Values are expressed as mean ± SEM. There is a significant difference between the two groups (P = 0.0003). Similar results were seen for normalization to ß-actin and PBGD gene expression.

A significant correlation was found between 11ß-HSD2 and PGDH mRNA concentrations (Fig. 3).

View larger version (18K): [in this window] [in a new window]   Figure 3. Significant correlation between 11ß-HSD2 and PGDH mRNA expression in all examined placentas (n = 58, r = 0.66, P < 0.0001). Triangles, Preeclampsia group; open circles, matched control group.

Birth weight and placental weight of term neonates correlated positively (r = 0.50, P = 0.01).

There was no difference in 11ß-HSD2 and PGDH gene expression of 10 preeclamptic patients with proteinuria and 8 patients without proteinuria (P > 0.05). In addition, no significant correlation was found among the mRNA levels of 11ß-HSD2 or PGDH and mother’s and gestational age. No relation was seen among systolic or diastolic blood pressure and 11ß-HSD2 or PGDH gene expression (P > 0.05). Comparison of preeclampsia patients with no, 1, or 2 antihypertensive drugs revealed no difference in 11ß-HSD2 or PGDH gene expression.

The mode of birth (spontaneous vaginal delivery or cesarean section) had no influence on either 11ß-HSD2 or PGDH gene expression.

To confirm the results obtained by TaqMan real-time PCR, competitive PCR for 11ß-HSD2 gene expression was performed in 14 placental samples of preeclampsia patients and matched controls, respectively. The differences in mRNA expression of 11ß-HSD2, compared with ß-actin, could be reproduced. TaqMan real-time PCR, preeclampsia vs. controls, 11ß-HSD2/ß-actin, 0.42 ± 0.06 RU and 1.13 ± 0.28 RU (P = 0.027); competitive PCR, preeclampsia vs. controls, 11ß-HSD2/ß-actin, 0.26 ± 0.13 RU and 1.0 ± 0.28 RU (P = 0.03).

	Discussion

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The present report is the first to use TaqMan real-time PCR for measuring 11ß-HSD2 and PGDH mRNA concentrations in human placenta of patients with preeclampsia. In previous studies, 11ß-HSD enzyme activity has been measured (3). However, the relative instability of the enzyme after cell disruption and assay conditions influence the preferred direction of 11ß-HSD action and create difficulties in the correct determination of this enzyme activity (6).

In contrast, real-time PCR provides direct data on the expression of the isoenzyme searched for. To control for similar amounts of tissue analyzed in the three groups of patients, three different housekeeping genes were used for normalization of gene expression. Thus, alterations of the concentration in a housekeeping gene do not explain the difference. Additionally, competitive PCR of the samples has confirmed the results obtained by real-time PCR concerning 11ß-HSD2 gene expression.

Three- and 2-fold reduction of 11ß-HSD2 and PGDH mRNA levels were found in placental tissue of patients with preeclampsia, compared with matched controls. Furthermore, both placental enzymes are not influenced by the process of labor itself or by the mode of delivery (12, 16). The impaired gene expression of 11ß-HSD2 elucidates the mechanism of reduced enzyme activity in preeclampsia that has been described previously (3).

During normal pregnancy, a physiological increase occurs in bound and free plasma cortisol levels (17). A function of 11ß-HSD2 is protection of the fetus from raising maternal glucocorticoid levels (10). The enzyme regulates access of glucocorticoid hormones to glucocorticoid and mineralocorticoid receptors within several target tissues, including the placenta (18). Hypertension and edema occurring in preeclampsia may be, in part, influenced by defective placental 11ß-HSD2 function. However, cortisol levels measured in maternal plasma did not differ in preeclampsia and normal pregnancies (3). It has been suggested that the defective 11ß-HSD2 activity is the consequence of a defect in placental development or an inhibitory substance of 11ß-HSD2 and possibly renal 11ß-HSD, as well, causing hypertension (3). From our data, we suggest that such a substance may influence transcription or stability of 11ß-HSD2 mRNA. In the literature, there is no information about the effect of antihypertensive drugs on placental 11ß-HSD or PGDH activity and gene expression in humans or other species. In rats, dihydralazine and methyldopa have been shown to be weak inhibitors of renal 11ß-HSD (19), whereas data in humans have not been published. From our data, no difference in the mRNA expression of either enzyme was detected, regardless of which antihypertensive drug was taken in preeclampsia patients.

In term neonates, birth weight correlates positively with 11ß-HSD2 gene expression. This relation might, in fact, be even underestimated as a consequence of the increasing statistical error when dividing two different measured values, as done with 11ß-HSD2 and the housekeeping genes. In fact, studies in rats have shown a similar relation between 11ß-HSD2 activity and fetal weight at term (20). Elevated placental cortisol levels resulting from a reduced 11ß-HSD2 enzyme activity in preeclampsia may contribute to impaired fetal growth (3).

In human placentas, a direct correlation of 11ß-HSD2 gene expression and placental weight was obtained, corresponding to the fact that fetal weight, at term, correlated with placental weight. However, in humans, other studies measuring 11ß-HSD2 enzyme activity could not confirm this relationship (3, 21).

Barker et al. (22) have postulated that adult humans with a history of low birth weight run an increased risk of developing hypertension. Likewise, the offspring of rats are at risk for hypertension and hyperglycemia when treated with the 11ß-HSD2 inhibitor carbenoxolone (23) or dexamethasone (20) during pregnancy. If impaired 11ß-HSD2 gene expression also manifests in the neonate, it may have an impact on blood pressure in the children of preeclamptic mothers.

Glucocorticoids inhibit PGDH activity in placental syncytiotrophoblast and chorion trophoblast cells in culture (11). Progesterone, however, increases PGDH mRNA expression in the placenta (24). It has been postulated that the effects of cortisol on PGDH activity are, at least in part, mediated by interaction of cortisol with the mineralocorticoid receptor suggesting that PGDH is a mineralocorticoid responsive gene (11, 25). We found a positive correlation among 11ß-HSD2 and PGDH mRNA levels and a reduced placental PGDH gene expression in patients with preeclampsia who have lower 11ß-HSD2 mRNA levels. It is conceivable that a similar effect of glucocorticoids found in vitro also leads to a down-regulation of PGDH gene expression in vivo. During normal pregnancy at term, elevated levels of cortisol displace progesterone from glucocorticoid receptors by competitive inhibition. This reduces PGDH transcription and activity, allowing PGs to reach the myometrium and to increase myometrial contractility (24, 26). Glucocorticoids also up-regulate PG H synthase type 2, further emphasizing their central role in coordinating parturition (27). Therefore, elevated placental cortisol levels in preeclampsia may lead, by an autocrine or paracrine mechanism, to a reduced PGDH gene expression, resulting in a decrease in PG metabolism. The present data on PGDH gene expression provide further pathophysiological evidence for the elevation of PGE₂ concentrations in placental tissue of patients with preeclampsia (28). This reduced PG metabolism may ultimately be involved in induction of preterm labor in preeclampsia.

In conclusion, our data demonstrate that placental gene expression of 11ß-HSD2 and PGDH is reduced in preeclampsia. Subsequent impaired metabolism of cortisol and PGs may be involved in impaired fetal growth and preterm delivery.

Received April 4, 2000.

Accepted November 1, 2000.

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