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INSERM U36-Laboratoire de Médecine
Expérimentale (C.H., J.M.G., P.C.) Collège de
France Paris, France 75005
Division Molecular Biology of
the Cell I (S.B., G.S.) German Cancer Research Center
Heidelberg, Germany
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ABSTRACT |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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MR is expressed with a much more restricted tissue distribution pattern than glucocorticoid receptors. Although both aldosterone and glucocorticoids bind to MR, MR occupancy in aldosterone target cells by aldosterone is ensured by the 11ß-hydroxysteroid dehydrogenase type II enzyme, which inactivates glucocorticoids. The presence of this enzyme is crucial for the specificity of aldosterone effects on target cells because glucocorticoids and aldosterone have an equivalent high affinity for the MR and glucocorticoids are much more abundant than mineralocorticoids (5, 6). Aldosterone acts by stimulating sodium reabsorption in epithelia of the colon and the kidney, via amiloride-sensitive epithelial sodium channels (7).
The essential role of MR in the processes of sodium balance has been recently documented by MR gene disruption in mice (8). The MR knockout mice MR-/-, obtained by gene targeting, died between day 8 and 13 after birth, with a markedly reduced weight and a severe dehydration due to failure of sodium reabsorption. The MR knockout mice showed all signs of pseudohypoaldosteronism, such as hyperkalemia, hyponatremia, and a strongly activated renin angiotensin system (RAS). Compared with wild-type mice, plasma renin was 440-fold, angiotensin II 50-fold, and aldosterone 65-fold increased.
The MR knockout mice also showed conspicious morphological changes at the glomerular vascular pole. The segment of the distal tubule at the level of the macula densa was enlarged, and the extraglomerular mesangium (juxtaglomerular cells) showed prominent hyperplasia. Renin-producing granular cells extended upstream along the afferent arteriole, and renin granules were seen in almost all extraglomerular mesangium cells in MR knockout mice.
In heterozygous mice MR+/-, the RAS was moderately activated. Compared with wild-type mice, plasma levels of renin, angiotensin II, and aldosterone were 2- to 3-fold increased, showing the adapted feedback response of the circulating RAS elements in an attempt to counteract the lack of aldosterone effects by partial MR deficiency (8).
This condition of extreme sodium depletion is unique in many aspects. Gene disruption of other components of the RAS do not produce such a severe and lethal phenotype. Angiotensinogen (AGT) knockout and angiotensin I-converting enzyme (ACE) knockout mice have a low perfusion pressure, renal insufficiency, and urinary concentration defect but can survive although Unemara et al. (9) reported that about 60% of the AGT knockout mice in their study did not survive until weaning. The stimulation of the RAS observed in the MR knockout mice is also much stronger than that observed in rodent models in which the RAS is stimulated, such as salt depletion induced by low sodium diet, furosemide, and (or) renovascular hypertension, reflecting the crucial role of salt reabsorption in the early days of life when the sodium intake from milk is limited (10).
It was therefore of interest 1) to further describe morphological changes induced by MR gene disruption in the kidney and the adrenal gland, two organs involved in sodium reabsorption and steroid biosynthesis, respectively; 2) to evaluate the expression of the different components of the RAS in these organs, but also in tissues where other components of the RAS are synthesized, such as the liver, lung, and heart; and 3) to determine whether the animals harboring a single MR allele exhibited any of the changes observed in MR knockout mice.
In MR knockout mice at age 8 days, at a time when the RAS is already functional, a marked increase in renin expression was found in the kidney and the adrenal gland, using mRNA semiquantification, in situ hybridization, and immunohistochemistry. An up-regulation of angiotensinogen in the liver was also observed, whereas ACE mRNA levels in the lung as well as in the heart were not altered. Except in the liver, angiotensin II receptor AT1 mRNA remained stable in heart, kidney, and adrenal gland.
The heterozygous mice exhibited a limited impairment of renal sodium reabsorption and a moderate 3-fold stimulation in plasma of renin, angiotensin II, and aldosterone levels compared with their concentrations in plasma of wild-type mice (8). However, compared with wild-type mice, the heterozygous mice showed no significant difference in any of the tested mRNA levels of the RAS components.
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RESULTS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Liver
AGT is a unique renin substrate and is mainly synthesized in the
liver. Expression of its mRNA was semiquantified by Northern blot and
normalized to the glyceraldehyde-3 phosphate dehydrogenase (G3PDH) mRNA
signal. In 8-day-old mice, AGT mRNA was increased by 12% in MR+/-,
and by 49% in MR-/-, compared with MR+/+ mice. Only the difference
between MR+/+ and MR-/- mice was statistically significant
(P < 0.01) (Fig. 1A
).
AT1 receptor is the only angiotensin II receptor expressed
in liver. Its mRNA level was evaluated by RT-PCR in the three
genotypes. AT1 expression increased by 145% in MR-/-
vs. MR+/+ mice (P < 0.01), whereas no
variation was observed in MR+/- mice (Fig. 1B).
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). Similarly, in situ
hybridization revealed no difference in expression of the ACE mRNA
among the three genotypes (data not shown).
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Kidney
In addition to the morphological changes at the glomerular
vascular pole in MR-/- mice described by Berger et al.
(8), we made the following observations. The wall of interlobar
branches of renal arteries was conspicuously thickened in MR-/- (Fig. 3, A and B). The degree of maturation of the kidney appeared
similar in mice of the three genotypes and, in particular, the number
and maturation stages of glomeruli did not grossly differ. In MR+/+
kidney, in addition to the juxtaglomerular apparatuses, immunoreactive
renin was detected in the innermost segments of proximal convoluted
tubules (PCT), whereas in MR-/-, renin was detected in PCTs in the
whole cortex, including the outermost region (not shown).
Interestingly, in MR-/- kidneys, renin-producing cells labeled by
immunohistochemistry (Fig. 3, panel D vs. panel C) as well
as by in situ hybridization (Fig. 3, panels I and J
vs. panels F and G), showed considerably enlarged
juxtaglomerular apparatuses, exhibiting an intensity of immunostained
renin not obviously above that observed in MR+/+ (Fig. 3, panel D
vs. panel C). No signal of renin mRNA could be detected in
the PCTs, whatever the genotype (Fig. 3, F and I). By RT-PCR analysis,
renin mRNA expression was 2.5-fold increased in MR-/- compared with
MR+/+ mice (P < 0.05), but not in MR+/-
(P = 0.7) (Table 1). Renin mRNA level, evaluated by
Northern blot and normalized to G3PDH mRNA level, showed a 10-fold
increase in MR-/- (P < 0.01) and again no change in
MR+/- mice (Fig. 2). No other
significant variations of ACE and AT1 mRNA between
genotypes were found by RT-PCR (Table 1). Similarly, using in
situ hybridization, there was no difference in the expression
level of AT1 receptor mRNA according to genotype (not
shown).
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), based on histological criteria, the
zona glomerulosa appeared thicker and extended more deeply toward the
medulla than in MR+/+ mice (Fig. 4A), to the detriment of the zona
fasciculata, which was reduced in thickness up to the point of being
histologically undetectable. This difference was not observed in
heterozygous animals. The expression of renin was investigated by
immunodetection and in situ hybridization. In MR-/-, a
clear hybridization signal for renin was located in the enlarged zona
glomerulosa (Fig. 4D). The labeling was not uniform and appeared in
cell clusters distributed within the thickened zona glomerulosa. In
heterozygous and wild-type (Fig. 4B) mice, renin mRNA remained below
detectable level. Renin was not immunodetected in the same adrenal
glands in which the renin mRNA level was high, although renin was
readily noticeable in glomeruli of the adjacent kidney (Fig. 3C). Because the adrenals were small,
particularly in 8-day-old mice, only two or three pools of organs could
be used for the RT-PCR and, therefore, no statistical analysis were
performed. A 10-fold increase of the normalized renin mRNA levels to
G3PDH was detected in MR-/- mutants compared with MR+/+ or MR+/-
mice (2.02, 0.22, and 0.17, respectively). No variation in
AT1 mRNA expression in 8-day-old mice was evaluated by
RT-PCR in MR+/+, +/-, and -/-, with relative values of 1.28, 1.28,
and 1.32, respectively, nor was there a variation in AT1
receptor mRNA levels by in situ hybridization. The other
isoform of angiotensin II receptors, AT2, appeared highly
expressed only in the medullary zone of the adrenal gland in MR+/+
(Fig. 4E) and to a lower level in MR-/-
animals (Fig. 4F). A 57% decrease in AT2 expression level
was measured by RT-PCR between MR+/+ and MR-/- with relative values
of 7.57 and 4.32, respectively. Incidentally, no expression of
AT2 mRNA was detected in the zona glomerulosa of mice of
the three genotypes.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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In addition to conspicuous changes at the glomerular vascular pole and the enlargement of the segment of the distal tubule at the macula densa level, we found, in MR-/- mice, a hyperplasia of the renal interlobar arteries (8). In animals with disruption of AGT (12, 21), ACE (14, 15), or both AT1A and AT1B genes (22), such renal artery hyperplasia was also noticed. These mice and MR-/- mice are likely to suffer from major renal hypoperfusion. The increase in vascular wall thickness is unlikely due to an increase in angiotensin II since AGT-/- and ACE-/- mice exhibit the same pattern without any detectable angiotensin II. This phenomenon may result rather from the stimulation of vascular growth factors provoked by the profound renal hemodynamic anomalies.
The adrenal gland of MR-/- mice was abnormal, with a marked increase in the zona glomerulosa, which may result from the trophic effect of high levels of angiotensin II, whereas the zona fasciculata was hardly detectable.
In this condition of unique neonatal sodium and volume depletion, it was of interest to evaluate the variations of expression of the components of the RAS in their main organs of production and in their target tissues. mRNA levels were assayed by Northern blot and/or RT-PCR and by in situ hybridization. The semiquantitative estimation of the different mRNAs was in good agreement with the qualitative in situ hybridization observations, although its main purpose was to identify the cells types affected.
The 0.5-fold increase in AGT mRNA expression in the liver of MR-/- mice is comparable to that observed in rat by a low sodium diet (23). This increase in AGT mRNA likely results from angiotensin II positive feedback, which has been shown to stimulate both AGT transcription and mRNA stability (24, 25).
The significant increase in renal renin mRNA expression observed in MR-/- animals varied between 2.5 and 10-fold according to the technique used. In AGT-/- mice, Tanimoto et al. (13) reported, by Northern blot analysis, a 6- to 8-fold increase in renin mRNA when compared with wild type animals. Renin mRNA is abundant in the hypertrophic juxtaglomerular apparatuses in MR-/- mice. Immunoreactive renin was detected in PCTs of the whole cortex, suggesting an intense renin reabsorption (26), as no renin mRNA was found in these structures. In this situation, renin mRNA is stimulated despite a marked increase in angiotensin II that is unable to fully down-regulate renin production (23, 27). In the MR-/- mice, as in salt-depleted rats, plasma renin levels are remarkably much higher than intrarenal renin content or mRNA level (28, 29). This discrepancy between intrarenal and circulating renin could be explained by a rapid release of newly synthesized renin related to a long half-life of renin mRNA.
The renin gene was intensely expressed in the adrenal gland in 8-day-old MR-/- mice and particularly in the zona glomerulosa. These observations are comparable to the effects of salt restriction in nephrectomized rats, where adrenal renin mRNA is increased (30), thus implicating the adrenal RAS in the regulation of mineralocorticoid biosynthesis (31, 32). Again, there was a discrepancy between the high level of renin mRNA and the absence of immunodetectable renin, which is likely due to the rapid secretion of renin by the adrenal gland. In the MR-/- mice, two factors may contribute to the marked expression of the renin gene, the increase in angiotensin II and (or) plasma potassium, but the relative contribution of these two mechanisms is still to be elucidated. Furthermore, how much adrenal renin could contribute to plasma renin is still unknown.
Opposite variations in rat AT1 mRNA expression have been reported in the literature during dietary sodium restriction, either in the liver, kidney, or adrenal gland (23, 33, 34, 35, 36). These discrepancies were still noticeable when the AT1A and AT1B subtypes were differentiated during the experiments. In 8-day-old MR-/- mice, the expression of AT1 receptor was slightly increased in the liver and unchanged in the kidney and the adrenal gland. These results are not in favor of a major effect of salt depletion on AT1 mRNA level. In this study the two AT1 receptors were not analyzed individually, and one cannot exclude a shift of one receptor isoform to another. However, such a phenomenon may have little physiological consequence since gene disruption of each isoform of AT1 receptor reveals that the two isoforms are interchangeable, at least to some extent (18, 37).
The changes in mRNA levels of the components of the RAS in 8-day-old MR-/- mice were not apparent in the heterozygous MR+/- mice. However, these animals have an increased urinary sodium loss, a 3-fold increase in sodium fractional excretion, and a modest compensatory stimulation of the circulating RAS, revealed by a 3-fold increase in renin, angiotensin II, and aldosterone levels compared with those in MR+/+. Altogether, this suggests a modest neonatal sodium loss, compatible with survival in the MR+/- mice. This mild sodium loss exhibited by these heterozygous mice is somewhat similar to the phenotype observed in patients with autosomal dominant pseudohypoaldosteronism type I (38). In these patients, with heterozygous defect in the MR gene, a modest form of neonatal renal salt wasting, with hyperkalemia and acidosis, was observed. The disease remits with age indicating the crucial importance of aldosterone-dependent sodium reabsorption in the postnatal period and its decreasing role with age (39).
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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RNA Preparation
Total RNA was isolated from various organs by the acid
guanidinium thiocyanate-phenol chloroform method (40). The
concentration of RNA was determined by measuring the absorbance at 260
nm, and its integrity was assessed by agarose gel electrophoresis.
Northern Blot
Total RNA was electrophoresed on 1.2% agarose denaturing gels
containing 2.2 M formaldehyde (41). The RNA was transferred
to charged Biohylon membrane (Bioprobe Systems, Montreuil, France) by
capillary blotting in 20 x SSC (1 x SSC: 0.15 M
sodium chloride, 0.015 M sodium citrate, pH 7).
Hybridization was carried out at 42 C for 18 h in 50% formamide,
40 mM Tris-HCl (pH 7.5), 350 mM NaCl, 1% SDS,
8 x Denhardt’s solution, 10% dextran, and 200 µg/ml salmon
sperm DNA, with full-length rat angiotensinogen cDNA (42) or mouse
renin cDNA (43). The probes were labeled with
[
-32P]dCTP (Amersham, Les Ulis, France) by the
multiprimer technique (44). The filters were washed at room temperature
for 30 min in 2 x SSC, 0.1% SDS, and finally in 1 x SSC,
0.1% SDS at 65 C. The filters were exposed to x-ray film at -80 C
with intensifying screen.
To normalize angiotensinogen and renin mRNA levels, the membranes were
rehybridized with a -32P-labeled G3PDH cDNA probe
(nucleotide position from 71 to 1053) (45). Autoradiographic signals
were quantified by scanning densitometry (Scanjet IICX; Hewlett
Packard, Palo Alto, CA). The results are expressed as the mean ±
SEM of triplicate determinations of the ratio of
angiotensinogen or renin mRNA to G3PDH mRNA levels.
Reverse Transcriptase Reaction and PCR Amplification
Total RNA (400 ng) of each organ or renal RNA (40 ng) for renin
expression were reverse transcribed in the presence of 50
mM Tris-HCl (pH 8.3), 30 mM KCl, 6
mM MgCl2, 10 mM dithiothreitol,
1.25 mM deoxynucleoside triphosphate, 20 U
ribonuclease (RNase) inhibitor (Promega, Charbonnieres, France), 100
pmol of random hexamer (Pharmacia, Orsay, France), and 20 U MuLV
reverse transcriptase (Boehringer Mannheim, Meylan, France) in 20 µl
at 37 C for 90 min. To minimize the variability between samples, for
each organ, all reverse transcriptions were conducted
simultaneously, including the three different genotypes. Primers used
for PCR were 20–24 nucleotides long, homologous to mouse species, and
did not exhibit 3'-complementary ends between primer pairs. The
sequences listed in Table 2 include
the respective positions in the cDNA sequences and the expected sizes
of the amplicons (43, 46, 47, 48, 49). The amplicons were further characterized
by rapid Southern blotting using internal oligonucleotides specific for
each mRNA (data not shown). For each set of primers, duplicate samples
were performed in a total volume of 25 µl. Three microliters of RT
reaction product were incubated in the presence of 10 mM
Tris-HCl (pH 8.3), 50 mM KCl, 3–5.5 mM
MgCl2, taking into account the DNA to be amplified,
200 nM of each 5'- and 3'-primer pairs, 0.5 mM
deoxynucleoside triphosphate, 3 µCi [-3H]dCTP
(Amersham), and 2.5 U of Taq polymerase (Boehringer
Mannheim). The appropriate cycle number, primer-annealing step, and
polymerization step were optimized for each selectioned cDNA. All
experiments were performed within the exponential phase of the reaction
taking into account the number of cycles and within the linear
curve response concerning the initial RNA amount.
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Within the same RT reaction, the ubiquitously expressed G3PDH mRNA was used to correct tube-to-tube variations in RT efficiencies. The ratio of the radioactivity of a considered cDNA to the radioactivity obtained for the G3PDH signal was calculated to express semiquantitatively the different mRNA levels.
In Situ Hybridization
The riboprobes used in this study were obtained by in
vitro transcription of cDNAs cloned or recloned in the laboratory.
We used a human renin cDNA (50), a rat angiotensinogen cDNA (42), a rat
ACE cDNA (51), and rat AT1 and AT2 cDNA (52, 53). The rat AT1 probe did not allow us to discriminate
between AT1A and AT1B mRNA since the coding
sequence of the available transcript subtypes is 90% identical in
nucleotide sequence. Consequently, the hybridization signal detected
both AT1 receptor subtype mRNAs. The transcription was made
from the T3, T7, or SP6 RNA polymerase promoter site of the plasmid
vector, after linearization with the proper enzyme, and in the presence
of [35S]UTP (Amersham). The technique of in
situ hybridization has been described in detail (54). Briefly,
paraffin sections were rehydrated and submitted to microwave heating at
100 C and to proteinase K digestion. Each section received 30–50 µl
of hybridization mixture containing approximately
104cpm/µl of 35S-labeled antisense or sense
riboprobe. Hybridization was at 50 C for 16 h. The
posthybridization washes included solutions of varying degrees of
stringency (from 5 xSSC with 50% formamide at 55 C to 0.1 xSSC at
room temperature) and a digestion with RNase A (20 µg/ml). The slides
were exposed on a Biomax MR film (Kodak, Marne La Vallee, France) to
obtain macroscopic autoradiographic pictures (1–3 days) and then were
dipped into NTB2 liquid emulsion (Kodak). At the end of the exposure
time (1–4 weeks), the slides were photographically processed and
stained with toluidine blue.
Immunohistochemistry
Renin and ACE were detected in kidney, lung, heart, and adrenal,
using primary antibodies produced in the laboratory (55, 56) and a
biotinylated secondary antibody revealed with the ABC-peroxidase
complex (Vector Laboratories, Burlingame, CA).
Statistical Analysis
Results are expressed as mean ± SEM.
Differences between means were analyzed by the nonparametric
Mann-Whitney U test for the comparison of wild-type MR+/+
animals and heterozygous MR+/- mutant mice and for comparison of MR+/+
and homozygous MR-/- mutant mice. Differences were considered
statistically significant at the P < 0.05 level.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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This work was supported in France by the Institut National de la Santé et de la Recherche Médicale and the Association Claude Bernard and in Germany by the Deutsche Forschungsgemeinschaft through Sonderforschungsbereich 229 and Boehringer Ingelheim 422/1–1, by the Fonds der Chemischen Industrie, by the European Community through Grant PL 960179, by the Bundesministerium für Bildung und Forschung through the Human Genome Project Grant 01 KW 9606/7, and by the Volkswagen-Stiftung.
Received for publication September 2, 1998. Revision received November 4, 1998. Accepted for publication November 9, 1998.
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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