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Experimental Studies |
and ß Messenger Ribonucleic Acid Isoforms of the Human Mineralocorticoid Receptor in Normal and Pathological States
INSERM U 246, Institut Féderatif de Recherche Cellules Epithéliales, Faculté de Médecine Xavier Bichat (M-C.Z., N.F., J-P.B., M.L.), 75870 Paris Cedex 18, France; and Clinica di Endocrinologia, Università degli Studi di Ancona, Ospedale Regionale di Torrette (M-C.Z.), 60100 Ancona, Italy
Address all correspondence and requests for reprints to: Marc Lombès, INSERM U 246, Institut Féderatif de Recherche Cellules Epithéliales, Faculté de Médecine Xavier Bichat, 16, rue Henri Huchard, BP416, 75870 Paris Cedex 18, France. E-mail: mlombes{at}bichat.inserm.fr
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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and 1ß), which splice
alternatively into the common exon 2, giving rise to two hMR mRNA
isoforms (hMR and hMRß). We have investigated expression of hMR
transcripts in renal, cardiac, skin, and colonic tissue samples by
in situ hybridization with exon 1 and 1ß specific
riboprobes, using an exon 2 probe as internal control. Specific signals
for either exon 1- and 1ß-containing mRNAs were detected in
typically hMR-expressing cells in all tissues analyzed. hMR and
hMRß were present in distal tubules of the kidney, in cardiomyocytes,
in enterocytes of the colonic mucosa, and in keratinocytes and sweat
glands. Interestingly, although both isoforms appear to be expressed at
approximately the same level, the relative abundance of each message
compared with that of exon 2-containing mRNA strikingly differs among
aldosterone target tissues, suggesting the possibility of other
tissue-specific transcripts originating from alternative splicing.
Finally, functional hypermineralocorticism was associated with reduced
expression of hMRß in sweat glands of two patients affected by
Conn’s and Liddle’s syndrome, whereas normal levels of hMR isoforms
were found in one case of pseudohypoaldosteronism. Altogether, our
results indicate a differential, tissue-specific expression of hMR mRNA
isoforms, hMRß being down-regulated in situations of positive sodium
balance, independently of aldosterone levels. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Recent determination of the human MR (hMR) genomic structure (16)
revealed the presence of two 5'-untranslated exons, which splice
alternatively into the common exon 2 containing the translation start
site. This gene structure is compatible with alternative promoters
directing expression of the 1 and 1ß messenger RNA (mRNA) isoforms
(hMR and hMRß, respectively), which might be regulated in a
tissue-specific and perhaps developmental manner (17). Indeed, we
recently demonstrated that the exon 1 and 1ß 5'-flanking regions
are functional promoters that differ both in their basal as well as
their hormone-regulated activities (18). Furthermore there is evidence
of tissue-specific expression of alternative MR mRNAs in the rat
(19).
To investigate the tissue-specific distribution of the two hMR
mRNA isoforms, we examined different human tissues by in
situ hybridization using hMR exon-specific cRNA probes. Our
results show that both exon 1- and 1ß-containing transcripts are
expressed in all aldosterone target cells examined. Interestingly,
although the two isoforms appear to be expressed at approximately the
same level in kidney and heart, their relative abundance compared with
the exon 2-specific signal strongly differs among these tissues. We
further examined the expression of hMR and ß isoforms in skin
biopsies from normal subjects and patients presenting with
mineralocorticoid-related sodium balance abnormalities. It appears from
our results that increased sodium reabsorption may influence hMRß
mRNA expression without affecting levels of hMR.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Small fragments of human tissues were obtained at surgery. Human kidney samples originated from the normal part of tumoral kidneys. Human heart fragments (left atrial appendage and papillary muscle of the mitral apparatus) were obtained during cardiac surgery for valve replacement. Skin samples were obtained from skin removed in the course of reparative or plastic surgery or from biopsies performed for diagnostic purposes. All fragments were fixed by immersion in Zamboni’s fixative (2% paraformaldehyde (wt/vol) 15% saturated picric acid (vol/vol), and 150 mM sodium phosphate, pH 7.4) for 24 h at 4 C. Samples were then dehydrated in graded ethanol solutions and embedded in paraplast.
Generation of hMR exon-specific probes
Fragments encompassing hMR exons 1 and 1ß were generated by
PCR using specific oligonucleotides as follows [S and A identify
primers in the sense and antisense orientation, respectively; numbering
corresponds to the position of the 5'-nucleotide according to the
transcription initiation sites as determined in (16)]: S3,
5'-TCTCAGCCCCTCCGCGCCCG-3' and A215, 5'-AGCGCTTGCCACCGCCACGAAAC-3'; S8,
5'-CCGCTGCCTCGCCGCCTCTTGTA-3' and A211, 5'-CTAGGACATGGTGGGGAGGCTGG-3',
for exons 1 and 1ß, respectively. The corresponding 212-bp and
203-bp PCR fragments were subcloned into pCR vector (Stratagene, La
Jolla, CA) and sequenced to exclude any misincorporation. After
linearization with either EcoRV or BamHI,
35S-labeled antisense and sense complementary RNA (cRNA)
probes were synthetized using SP6 or T7 polymerase (Promega, Madison,
WI), respectively. The exon 2-specific probes correspond to a
ScaI fragment of the hMR complementary DNA [nt177–982,
nucleotide 1 corresponding to the first nucleotide of exon 2 (16)]
inserted into pGEM vector (Promega). 35S-d-Uridine
triphosphate (>37 Tbq/mmol) was from Amersham (Arlington Heights, IL),
and the other reagents [Trinucleotides, ribonucleasin, dithiothreitol
(DTT), RNA polymerase] were from Promega.
In situ hybridization
Human tissues sections (5–7 µm) were cut, mounted on subbed slides, and processed for in situ hybridization as previously described (20). After xylene removal of paraplast, the sections were rehydrated and postfixed in 4% paraformaldehyde for 20 min and rinsed with PBS. Proteinase K treatment (20 µg/ml) was followed by an acetylation step (0.1 M triethanolamine, pH 8.0, 0.025% acetic anhydride). The sections were rinsed in PBS and saline and then dehydrated and dried. Hybridization mix was spread over the sections. Hybridization was performed overnight at 50 C. Posthybridization treatment consisted of an initial wash in 5x SSC, 10 mM DTT at 50 C, a high-stringency wash in 50% formamide, 2x SSC, 0.1 M DTT at 65 C for 20 min, and two 10-min washes in 10 mM Tris-HCl, 0.5 M NaCl, 5 mM EDTA at 37 C. Ribonuclease A treatment (20 µg/ml) was performed at 37 C for 20 min. Sections were rinsed with 0.1x SSC, dehydrated in graded ethanol containing 0.3 M ammonium acetate, and dried. Kodak NTB2 film (Eastman Kodak, Rochester, NY) melted at 42 C was applied to the slides, dried, and exposed at -20 C for 6 weeks. The film was developed (Kodak D19) and fixed (Kodak Unifix). The sections were counterstained with toluidine blue.
Quantification of in situ hybridization signals
Hybridization signals of darkfield images were quantified using image analysis (Optilab, Graftek, Voisin Le Bretonneux, France). For each tissue section, a brightfield image was used to delineate the structure in which the hybridization signal had to be quantified. The delineated area was then superimposed on the darkfield image of the same zone, and the optical density of the silver grains was measured. Background measured on a zone devoid of tissue was deducted from tissue labeling to calculate specific hybridization signal. Analysis was performed on at least three high-power fields of different sections of tissue samples deriving from at least four different patients. Results are given in arbitrary units per surface area. Specific signals were the difference between antisense and sense conditions. Statistical analyses were performed using ANOVA, Student’s t test, and nonparametric Wilcoxon’s test, using the computer software InStat version 2.01 for Macintosh (GraphPad Software, San Diego, CA).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and ß hMR mRNA isoforms in human tissues
To study individual expression of each hMR mRNA isoform, we
constructed cRNA probes mapping to exon 1 and 1ß. Exon 2-specific
cRNA probes were synthetized and used in parallel experiments as
internal standard. Figure 1
shows results obtained after
hybridization of human renal cortex with antisense and sense hMR
exon-specific probes. As expected, use of the exon 2-specific probe
yielded a clear labeling over the typically mineralocorticoid-sensitive
distal tubules (Fig. 1A), whereas no specific signal could be detected
in the proximal tubules or in the glomeruli. After hybridization of
renal cortex sections with 1 and 1ß exon-specific antisense probes
(Fig. 1, B and C), the same structures, i.e.
distal convoluted tubules and cortical collecting ducts, were
positively labeled, indicating that both hMR mRNA isoforms were
expressed within the same cells. Because hMR expression is relatively
low, long exposure time was required (6 weeks) resulting in some
unspecific hybridization signals (background) as visible with the sense
probes (Fig. 1, D-F). Nevertheless, the signals observed with sense
probes were always lower than those obtained with the corresponding
antisense probes and uniform over the tissue section.
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), whereas the small intracardiac vascular structures
were devoid of any specific signal (not shown). Interestingly,
cardiomyocyte labeling was very strong when using exon 1 and 1ß
antisense probes (Fig. 2, B and C). Although the background levels
obtained with the corresponding sense probes were somewhat high (Fig. 2, E and F), specific signals for and ß hMR mRNA isoforms were
clearly higher than those given by the exon 2-specific probe.
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and 4 illustrate hMR mRNA detection in
the human skin. Epidermal sections presented a strong labeling with all
antisense probes (Fig. 3, A-C), whereas cells of the dermis were not
specifically labeled; sense signals were clearly lower (Fig. 3, D-F).
Sweat glands presented an intense specific signal with the exon 2
antisense probe as well as with the exon 1- and 1ß-specific probes
(Fig. 4, A-C), whereas sense signals were low (Fig. 4, D-F). These results indicate that both hMR mRNA isoforms are
coexpressed in keratinocytes and cells of sweat gland ducts.
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and ß mRNA was also evidenced in enterocytes
of the colonic mucosa (not shown). Differential expression of hMR isoforms among aldosterone target cells
To estimate the relative abundance of each hMR isoform in a
particular tissue and to compare their prevalence from one structure to
another, we quantified hybridization signals by image analysis. Figure 5 presents the quantification strategy in a human kidney
section hybridized with exon 2-specific probes. Optical densities of
the silver grains of darkfield images were measured for both antisense
(Fig. 5, A and B) and sense (Fig. 5, C and D) probes to calculate
specific hybridization signal. Although the absolute amount of each hMR
mRNA species cannot be precisely measured by this technique because of
the use of different probes, direct comparison of the analysis results
becomes possible within the same series of experiments, because tissue
sections are subjected to the same hybridization protocol,
e.g. identical probes with the same specific activity, same
hybridization time, washes, and film exposure times, ensuring validity
of this approach.
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. Although mRNA levels can be compared among different
tissues hybridized with the same probe, comparison between results
obtained with different probes (exon 2, 1 and 1ß) should be
interpreted with caution, because signal intensity depends on the
length of the probe, its nucleotide composition, and its secondary
structure. As expected, kidney distal tubules and sweat glands
contained the highest levels of hMR mRNA detected with the exon
2-specific probe; lower values were observed in keratinocytes and
cardiomyocytes. This contrasts with the pattern of expression observed
using the exon 1 and 1ß probes, which gave equivalent
hybridization signals in all tissues, except for the higher levels of
exon 1ß-containing transcripts in sweat gland ducts. Thus, it appears
that hMR mRNA levels detected using probes corresponding to
untranslated exons 1 and 1ß do not correlate with values obtained
with the exon 2-specific probe. Furthermore, the relative abundance of
each isoform differs among aldosterone target tissues.
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We took advantage of the availability of some skin biopsy
fragments from three patients presenting with clinical and biological
mineralocorticoid abnormalities, i.e. a patient with Conn’s
syndrome, one with type I pseudohypoaldosteronism, and one with
Liddle’s syndrome. Table 1 shows the results of
quantification in epidermis and sweat gland ducts of these patients.
Although levels of hMR and hMRß detected in keratinocytes were
comparable with those of normal subjects, the two patients affected by
primary hyperaldosteronism and Liddle’s syndrome had significantly
reduced expression of hMRß in sweat glands, compared with that of
normal controls. It should be noted that expression of hMR was not
modified in these patients. In contrast, no major abnormality in hMR
expression pattern was observed in pseudohypoaldosteronism. From these
results, it may be proposed that excessive sodium reabsorption might
influence expression of hMRß, perhaps in a tissue-specific
manner.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and hMRß (16), by in
situ hybridization, using specific probes corresponding to the
untranslated exons 1 and 1ß. We also used a probe located in exon
2, which contains the translation start site and is common to both hMR
transcripts. Consistent with previous studies, hMR mRNA was detected in
the distal parts of the nephron, cardiomyocytes, colon, and sweat gland
ducts and keratinocytes of the epidermal layers of the skin. The
relative level of hMR transcripts detected with the exon 2 probe, as
measured by computer-assisted densitometry, was as follows: kidney
= sweat glands > colon > epidermis > heart. More
importantly, we provide evidence that both 1- and 1ß-containing
hMR mRNA are present in all aldosterone target cells examined and are
apparently expressed at approximately the same level. This expression
pattern is in contrast with recent studies by Kwak et al.,
who reported a large prevalence of rat MR over MRß mRNA in rat
kidney, using an RNase protection assay (19). In their study, both
isoforms were apparently equally expressed in rat hippocampus, whereas
MR mRNAs levels in heart and skin were not examined. This discrepancy
could be accounted for by the particular quantification method used,
but more likely might represent species-specific differences in MR
expression. Preliminary results from our laboratory using an RNase
protection assay suggest equivalent expression of and ß hMR mRNA
in human kidney.
One main issue arises from our results. Although expression of both
exon 1- and 1ß-containing hMR transcripts does not appear to vary
among aldosterone target tissues (with the exception of sweat glands),
marked differences in the level of hMR mRNA as detected by exon 2 probe
(specific for an exon common to both isoforms) are found. Furthermore,
although in kidney the signals corresponding to 1 and 1ß mRNAs
were clearly lower than that given by the exon 2-specific probe,
expression of individual 1- and 1ß-containing transcripts was much
higher than that of exon 2 in the heart. Altogether, our results
suggest the existence of other hMR mRNAs, not detected by an exon
2-specific probe, which might arise from tissue-specific alternative
mRNA splicing (22). Because exon 2 contains the translation start site
of hMR, it might be important to determine whether hMR mRNA variants
led to the same translational product or whether alternative splicing
produce distinct, tissue-specific, hMR proteins. Moreover, we have
recently identified in the 5'flanking region of the hMR gene (18), a
sequence highly homologous to another 5'-untranslated exon (1
) of
the rat MR (19), suggesting the existence of other 5'-untranslated
variants in humans. However, previous results obtained by rapid
amplification of cDNA ends (RACE) (16), as well as preliminary attempts
to identify such transcripts in human kidney, indicate that they might
represent extremely minor species. In any case, it may be important to
determine whether hMR mRNA isoforms differ by their relative stability
rates of translational initiation, translational efficiency, and/or
degradation susceptibility. All the above parameters influence mRNA
levels and receptor expression.
It was interesting to examine whether regulation of hMR isoform
expression could be evidenced in subjects presenting with different
diseases affecting the mineralocorticoid transduction pathway. Indeed,
little information is available concerning hMR regulation in humans.
Using binding experiments, Armanini et al. (14, 15) showed
down-regulation of hMR in mononuclear leukocytes in different types of
hyperaldosteronism. Because of the ethical difficulty and technical
problems of obtaining access to classical aldosterone target tissues in
humans, the study of hMR expression in skin biopsies represented an
alternative approach. Analysis of biopsies from affected subjects
revealed a significant reduction of exon 1ß-containing transcripts in
the sweat gland ducts of a patient presenting with Conn’s and a
patient with Liddle’s syndrome, whereas levels of hMR mRNA were
normal. Both diseases are characterized by an increased renal sodium
reabsorption associated with extracellular volume expansion and
hypertension, resulting from increased aldosterone production and from
constitutive activation of the amiloride-sensitive epithelial sodium
channel (23, 24, 25), respectively. Although no definite conclusion can be
drawn, in particular because of the very limited number of patients, in
the presence of a positive sodium balance, the expression of exon
1ß-containing transcripts seems to be down-regulated in
sodium-reabsorbing epithelia. This regulation occurs independently of
absolute aldosterone levels, which are suppressed in Liddle’s syndrome
and high in Conn’s syndrome. In contrast, hMR mRNA appears to be
normal in the subject affected by the dominant form of type I
pseudohypoaldosteronism, which is characterized by mineralocorticoid
resistance, despite high circulating aldosterone levels (26). These
results are consistent with previous observations of normal hMR mRNA
expression in lymphocytes from affected patients, as determined by
semiquantitative RT-PCR analysis (27, 28).
In terms of hMR regulation, it thus appears that receptor status is not directly correlated to absolute aldosterone levels. From our data, it seems that an enhancement of transepithalial vectorial sodium transport across polarized epithelia may be responsible per se for the observed reduction in hMRß mRNA expression. The regulatory pathways and molecular events involved remain to be established. However, we recently showed that hMR gene expression is controlled by two distinct promoters (18). It is worth noting that in vitro the mineralocorticoid signal transduction pathway modulates activity of the exon 1ß 5'-flanking region, corresponding to the distal hMR promoter, whereas the proximal promoter is not submitted to this type of regulation.
In summary, we provide evidence that both 1- and 1ß-containing hMR
mRNA are expressed in aldosterone target tissues. However, their
relative abundance varies in a tissue-specific manner, and their
expression seems to be differentially affected by sodium overload. Our
findings also suggest the existence of novel hMR isoforms specific to
certain aldosterone target cells, and might provide an in
vivo model to discern regulatory mechanisms of hMR expression and
their involvement in human disease.
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Acknowledgments |
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Footnotes |
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Received November 7, 1996.
Revised January 8, 1997.
Accepted January 29, 1997.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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subunit: genetic heterogeneity of Liddle’s syndrome. Nature Genetics. 11:76–82.[CrossRef][Medline]
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