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Original Studies |
Departments of Medicine (J.C., M.H., P.M.S.) and Pathology (A.J.H.), University of Birmingham, Queen Elizabeth Hospital, Birmingham, United Kingdom B15 2TH; and the Department of Obstetrics and Gynecology, University of Liverpool, Liverpool Womens Hospital (C.G., D.G., P.N.), Toxteth, Liverpool, United Kingdom L8 7SS
Address all correspondence and requests for reprints to: Prof. Paul Stewart, M.D., F.R.C.P., Department of Medicine, Queen Elizabeth Hospital, Edgbaston, Birmingham, United Kingdom B15 2TH. E-mail: p.m.stewart{at}bham.ac.uk
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Abstract |
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The data indicate that 11ßHSD2 in fetal life principally modulates ligand access to the GR in most fetal tissues, notably glomeruli and tubules in the developing kidney, testis, and periderm, and this may be have ramifications for fetal sodium homeostasis and differentiation. The development of tissues previously shown to have a critical requirement for glucocorticoids, such as lung and adrenal medulla, is facilitated by the expression of GR mRNA, but not 11ßHSD2. The expression of MR mRNA in high abundance in bone suggests a role for corticosteroids in human bone development, and the low/absent expression of 11ßHSD2 at this site suggests that it is functionally acting as a GR.
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Introduction |
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11ßHSD2 is also expressed in human fetal tissues, including the placenta (9, 10, 11). Its function in these tissues is uncertain, although its expression in the placenta may serve to protect the developing fetus from the potentially deleterious effects of much higher concentrations of maternal glucocorticoids (12). Glucocorticoid excess in utero has been proposed as an underlying mechanism explaining the epidemiological link between birth weight (and by inference fetal growth) and the subsequent development of hypertension in adult life (13, 14). By contrast, certain tissues, for example lung and adrenal medulla, have a critical requirement for glucocorticoid during development (15). Furthermore, at least in early fetal life before the full functional development of the kidney and gastrointestinal tract, tissues such as the placenta and skin may be responsible for regulating sodium homeostasis within the fetus.
Using complementary ribonucleic acid (cRNA) probes against the human MR, GR, and 11ßHSD2 and an in-house 11ßHSD2 antiserum, we have examined the expression of these ligands in human fetal tissues from gestational ages 6–17 weeks.
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Materials and Methods |
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Collection and processing of human fetal material were approved by the district and local hospital ethical committees and collected according to the Polkinghorne code of practice and full patient consent (16). Fetal material was collected from elective surgical terminations of gestational age 6–17 weeks (n = 15 in total). For each window of gestational age studied (6+, 8–10, 12, and 16 weeks), a minimum of three separate fetuses were studied. Determination of fetal age was defined by ultrasound measurements, crown to rump length, and heel to toe length measurements (17). Material was treated with 50 mL heparin immediately posttermination to prevent blood clotting. Fetal and maternal tissues were separated through sterile sieves using sterile instruments. Fetal tissues were placed on ice, identified, and either snap-frozen or fixed in fresh 4% paraformaldehyde.
Synthesis of digoxigenin-labelled cRNA probes: 11ßHSD2, MR, and GR probes
Human 11ßHSD2, MR, and GR cRNA probes were synthesized from full-length human clones donated by Drs. Krozowski (18), Arriza (4), and Hollenberg (19), respectively. Suitable fragments of the above clones were isolated by restriction digestion and subcloned into TA vector systems, 11ßHSD2 into PCR3.1 (Invitrogen, Leek, The Netherlands) and MR and GR into pGEM T (Promega Corp., Southampton, UK). For the human GR this was a 693-bp fragment encompassing nucleotides 808-1501 of the published complementary DNA, for MR this was a 450-bp fragment (nucleotides 2590–3040 of the complementary DNA), and for 11ßHSD2 this was a 607-bp fragment (nucleotides 607-1497). The GR and MR probes shared less than 10% homology. Digoxigenin-UTP-labeled cRNA probes were synthesized by in vitro transcription using the appropriate restriction enzymes and SP6 T7 RNA polymerases (Boehringer Mannheim, Lewes, UK). Specifically, antisense cRNA probes for 11ßHSD2 were synthesized using T7 polymerase after linearization with ApaI; MR and GR antisense cRNA probes were synthesized using SP6 polymerase after linearization with ApaI. 11ßHSD2 sense cRNA probes were synthesized using SP6 polymerase after linearization with HindIII; for GR and MR, T7 polymerase was used after linearization with NotI. The nonradioactive digoxigenin RNA labeling and detection system (Boehringer Mannheim) allowed the detection of 0.1 µg homologous RNA (20).
In situ hybridization
Sagittal 5-µm sections from the paraformaldehyde-fixed tissue blocks were mounted onto 3-amino propyl triethoxysilane-coated slides under ribonuclease-free conditions, dewaxed in serial dilutions of alcohol, and subjected to 30 min of 10 µg proteinase K in 50 mmol/L Tris at 37 C. Sections were incubated with the 11ßHSD2, MR, and GR probes diluted in Hybrisol VI (Oncor Appligene, Hertfordshire, UK) overnight at 58, 42, and 45 C, respectively. The sections were subjected to a series of stringent posthybridization washes. Visualization of the probe was achieved by immunological colorimetric detection, with an alkaline phosphatase-conjugated antidigoxigenin antibody (polyclonal, Fab from sheep) and 5-bromo-4-chloro-3-indolylphosphate/nitro-blue tetrazolium reaction.
Immunohistochemistry
Sagittal 5-µm sections from the paraformaldehyde-fixed tissue blocks were mounted onto 10% poly-L-lysine-coated slides and dewaxed in serial dilutions of alcohol. Sections were treated with 30% hydrogen peroxide in methanol to block any endogenous peroxidase activity and were washed with 0.1 mol/L phosphate-buffered saline with 0.1% BSA. Slides were incubated with a 1:100 dilution of antibody derived against human 11ßHSD2 as previously reported (21) for 60 min, washed in phosphate-buffered saline and BSA as before, and incubated with a 1:100 dilution of an antidonkey sheep horseradish peroxidase conjugate (The Binding Site, Birmingham, UK) for 30 min. Staining was visualized using diaminobenzidine, and sections were counterstained with hemotoxylin. In each immunocytochemical study, negative controls included tissues known to be devoid of 11ßHSD2 expression (e.g. human adult liver), sections in which the primary antiserum was omitted, and sections in which the primary antiserum was preadsorbed with the original immunizing peptide (21).
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Results |
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and Table 1).
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and 3). Thus, in the kidney, 11ßHSD2 and GR
expression was highest in the developing glomeruli, central collecting
duct, and the epithelial cells of some renal tubules, both proximal and
distal in origin (Figs. 2a and 3, c and d). In contrast, very little MR
mRNA was present in extratubular sites. No hybridization was seen to
control sense cRNA probes (Fig. 2b). This pattern of distribution was
most marked at fetal age 12 weeks. Here intense 11ßHSD2 and GR
expression, but not MR mRNA, was observed over Bowman’s capsule and
the vascular tufts of developing glomeruli as they migrated from the
surface of the kidney into the inner cortex. Expression of both
11ßHSD2 and the GR was markedly reduced in fully differentiated
glomeruli (Fig. 3, c and d). 11ßHSD2 mRNA was also colocalized to MR
mRNA within epithelial cells of renal collecting ducts (Fig. 3c). By 16
weeks gestational age the renal expression of 11ßHSD2 had taken on a
more adult pattern, with expression seen over collecting duct
epithelial cells where it colocalized predominantly with MR mRNA (Fig. 4c). 11ßHSD2 expression, however,
together with GR mRNA was still observed over developing glomeruli in
the outer cortex of the kidney.
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) and periderm (Fig. 3e), gut, sex chords of the testis (Fig. 4, a
and b), and adrenal (Fig. 5). One obvious
exception was bone, where expression of 11ßHSD2 mRNA was low in
contrast to the marked expression of MR mRNA (Figs. 1c and 3a). MR mRNA
was found in chondrocytes of developing ribs (Fig. 3b) and the
perichondrial border, encompassing osteoblasts and chondrocytes in
developing long bones (Fig. 3a) until 16 weeks gestation. After this
gestational age the pattern of distribution of the MR was more adult in
nature, with highest levels found in kidney, periderm, and colon where
colocalization with 11ßHSD2 could be seen (Fig. 4, b and c). Broadly
speaking, within fetal tissues at this gestational age there was a
close correlation between GR and 11ßHSD2 expression. Exceptions to
this were the lung and possibly chromaffin tissue within the adrenal
medulla, both of which had high levels of GR mRNA, but low levels of
11ßHSD2 (Figs. 4d and 5). GR, MR, and 11ßHSD2 mRNA was present in
neural tissue of the spinal cord and dorsal root ganglia (Fig. 3b);
brain tissue was not available for analysis.
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, a, c, and e). Within the colon and
periderm, 11ßHSD2 immunoreactivity was also evident in surface
epithelial cells (Fig. 6, b and d). In the adrenal, however, 11ßHSD2
mRNA was found only in the outer definitive zone (Fig. 5), whereas
immunoreactivity was seen only in the inner fetal zone, excluding
adrenal medullary rests (Fig. 6f).
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Discussion |
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Within individual fetal tissues, striking and temporal patterns of 11ßHSD2, MR, and GR mRNA expression were observed. Before 16 weeks gestational age, the expression of 11ßHSD2 mRNA was closely related to that of GR, notably in the glomeruli, periderm, sex chords of the testis, muscle, and adrenal, suggesting that 11ßHSD2 principally serves to regulate cortisol exposure to the GR at these sites. Before keratinization at 17–20 weeks gestation, the cells within the periderm contain microvilli and can transport urea, creatinine, and sodium (36). This may represent an important mechanism by which the fetus maintains sodium and water balance before functional development of the kidneys and gastrointestinal tract, and our data suggest that this is predominantly glucocorticoid, rather than mineralocorticoid, regulated. Alternatively, glucocorticoids may play an important role in the differentiation and development of skin and other tissues expressing the GR; 11ßHSD2, in turn, may regulate this process.
This concept was illustrated best in the fetal kidney. At the earliest stage of development studied, the mesonephros, which may act as a functional kidney before the appearance of the metanephros, only expressed MR mRNA, suggesting that the receptor is unprotected at this stage. The metanephros develops from two components: the ureteric bud, which induces the mesenchymal blastema to form an epithelial condensation, which, in turn, induces dichotomous branching of the ureteric bud. The epithelial renal vesicle grows into an S-shaped convoluted tubule with a hook-shaped Bowman’s capsule, and the capillary tuft or glomerulus becomes linked to the vascular system. The ureteric bud gives rise to the renal pelvis, calices, and collecting ducts, whereas the S-shaped tubule differentiates into proximal and distal tubules. By 10 weeks gestation and thereafter, MR mRNA was only localized to structures derived from the ureteric bud, that is collecting ducts. In contrast, high levels of 11ßHSD2 were found in both components of the metanephros; proximal, distal, and collecting tubules; Bowman’s capsule; and, most striking of all the developing glomeruli, where colocalization with GR mRNA was seen. This pattern of distribution is similar to that reported for vascular endothelial growth factor (VEGF), an important regulator of endothelial cell proliferation and migration (37). Recombinant-derived mice lacking the VEGF gene demonstrate abnormal nephron development, with glomeruli lacking capillary tufts (38). VEGF is a glucocorticoid-dependent gene product, and it is interesting to speculate that the effects of glucocorticoids on renal development may be mediated through VEGF (39). Renal function and morphology has not to our knowledge been reported in mice lacking the GR gene (15).
Three other tissues warrant mention: lung, adrenal, and bone. Normal lung development is characterized by a glandular proliferation phase between 8–19 weeks gestation during which there is gland-like duct growth with successive branching of ducts to form terminal sac-like canaliculi capable of forming alveoli. In the bronchial branches, columnar epithelium differentiates into ciliated epithelium. Intense GR mRNA expression was observed over all these structures from gestational age 8–17 weeks in this study. In contrast, much lower levels of 11ßHSD2 and MR mRNA were seen only in bronchial columnar epithelial cells. Mice lacking the GR gene are known to have impaired development of the terminal bronchioles and alveoli (15). Lung dysplasia was also observed in mice lacking CRF, and this could be reversed by prenatal glucocorticoid administration (40). Glucocorticoids are known to regulate the production of the surfactant proteins SP-A, SP-B, SP-C, and SP-D (41, 42) and the apical sodium channel (43), both of which may be important events in lung inflation at birth. Our findings of high levels of GR mRNA together with relatively low levels of 11ßHSD2 would facilitate high local concentrations of glucocorticoids, which are required for normal lung development.
The same principle may apply for the adrenal medulla. The adrenal
originates from the coelemic epithelium between the gastric mesentery
and mesonephros. From 8 weeks on, two distinct zones can be identified:
an outer narrow progenitor layer, the neocortex or definitive zone, and
an inner fetal zone. Neural crest-derived chromaffin cells invade the
gland from gestational age 6 weeks on and differentiate by 8 weeks of
age, but a morphological adrenal medulla is not formed until the
neonatal period (44). The huge relative size of the fetal adrenal
compared to its adult counterpart can be explained predominantly by the
large fetal zone that synthesizes dehydroepiandrosterone
sulfate, the precursor for maternal estrogen throughout
pregnancy. Because of a relative deficiency of 3ß-HSD in both zones
of the fetal adrenal (45), the adrenal would require
progesterone for cortisol production. High levels of
progesterone in the fetal circulation (46) together with
the expression of both 17
- and 21 hydroxylases in the fetal zone
(47) suggest that cortisol is indeed synthesized by the fetal adrenal.
The expression of 11ßHSD2 within the fetal adrenal is therefore
puzzling. Firstly, this appears to be the only example reported to date
where there exists a discrepancy between the sites of 11ßHSD2
synthesis and expression; 11ßHSD2 is transcribed in the outer
progenitor layer, but is only expressed in the inner fetal zone.
Secondly, it remains unclear as to why the fetal zone, if it is indeed
synthesizing cortisol, would effectively inactivate it. Glucocorticoids
are known to be an essential requirement for normal adrenal
development, specifically the development of the adrenal chromaffin
cells (15) and the expression of phenylethanolamine
N-methyltransferase (48). In keeping with these data, GR
mRNA (but not MR mRNA) was ubiquitously distributed in both zones of
the adrenal in addition to chromaffin cells scattered throughout the
cortex. Chromaffin cells within the fetal zone did not express
11ßHSD2, which again would facilitate high glucocorticoid
concentrations within these cells.
Finally, of some interest was the expression of high levels of MR in developing long bones and ribs. Expression appeared to be highest in osteoblasts, at bone-forming sites. Levels of GR and 11ßHSD2 mRNA were much lower, but they also appeared to be localized to osteoblasts. In adult bone, several studies have demonstrated the expression of functional GRs (49), and we have recently identified specific aldosterone binding in some rat osteoblastic cell lines (50). The function of MR in developing bone, however, remains unknown.
Our data suggest therefore that corticosteroids will play a crucial role in the development and differentiation of many fetal tissues, and the expression of 11ßHSD2 may be a pivotal mechanism in this process. In particular, the expression of GR in developing glomeruli, testis, and skin may be of importance in normal renal and gonadal development and fetal sodium homeostasis; at these sites cortisol exposure to the GR is clearly modulated by 11ßHSD2 expression. In contrast, GR expression in the fetal lung and in adrenal chromaffin cells is not protected by 11ßHSD2. Similarly, at some sites (e.g. bone) and in early gestation (<8 weeks), the expression of MR and the absent expression of 11ßHSD2 suggest that the MR may be acting as a functional GR. By 16 weeks gestation a more adult pattern of expression of 11ßHSD2 and MR is observed, with colocalization in epithelial cells of the colon and collecting ducts.
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Footnotes |
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2 Medical Research Council Senior Clinical Fellow.
Received May 4, 1998.
Revised August 7, 1998.
Accepted September 1, 1998.
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