1 Section on Pharmacology, National Institute of Mental Health, Bethesda, Maryland 20892; and 2 Vanderbilt University, Department of Biochemistry, School of Medicine, Nashville, Tennessee 37232
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ABSTRACT |
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The
proposed feedback between angiotensin II AT2 and
AT1 receptors prompted us to study AT1 receptor
expression in kidneys of male AT2 receptor-gene disrupted
mice (agtr2 /y). In wild-type (agtr2 +/y) mice,
AT1 receptor binding and mRNA is abundant in glomeruli, and
AT1 receptor binding is also high in the inner stripe of
the outer medulla. AT2 receptors are scarce, primarily associated to cortical vascular structures. In agtr2
/y
mice, AT1 receptor binding and mRNA were increased in the
kidney glomeruli, and AT1 receptor binding was higher in
the rest of the cortex and outer stripe of the outer medulla, but not
in its inner stripe, indicating different cellular regulation. Although
AT2 receptor expression is very low in male agtr
2 +/y mice, their gene disruption alters AT1 receptor
expression. AT1 upregulation alone may explain the
AT2 gene-disrupted mice phenotype such as increased blood pressure, higher sensitivity to angiotensin II, and altered renal function. The indirect AT1/AT2 receptor
feedback could have clinical significance because AT1
antagonists are widely used in medical practice.
renin-angiotensin system; angiotensin II receptor types; gene-disrupted models
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INTRODUCTION |
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ANGIOTENSIN II (ANG II), by stimulation of specific, discretely localized ANG II receptors, plays a crucial role in the modulation of renal function in mammals (31). ANG II receptors are classified into AT1 and AT2 types on the basis of their relative affinity for nonpeptidic-selective ligands (46) and molecular cloning (16, 19, 39). Most of the known actions of ANG II on the regulation of water and salt metabolism are dependent on stimulation of AT1 receptors (31, 46). In the kidney, stimulation of AT1 receptors by ANG II modulates both glomerular and tubular function including sodium retention, vasoconstriction of renal vessels, and decreased glomerular filtration rate (2).
AT1 receptors are present in large numbers in the adult mammalian kidney, with a major expression in the glomeruli, and lower levels in the renal cortical tubules, vasculature, medullar interstitial cells, and collecting ducts (1, 4, 6, 22, 23, 30, 36, 38, 40). Of the two AT1 receptor subtypes existing in rodents, AT1A and AT1B, the AT1A receptors predominate in the kidney (22). In adult rodents, kidney AT2 receptors were reported to be absent (4, 23, 41) or present at low levels (18, 38). Other studies reported a selective association of AT2 receptors in the adult kidney from different species, including humans, with vascular structures (8, 9, 10, 30, 49). The localized and restricted expression of AT2 receptors in association with renal arteries strongly suggested a function of AT2 receptors different from that of AT1 receptors, perhaps related to inhibition of angiogenesis and vasodilation (3, 34).
The availability of animal models with targeted disruption of specific genes provided an opportunity to further analyze the possible role of AT2 receptors. The targeted disruption of the mouse AT2 receptor gene significantly increased blood pressure and the sensitivity to the pressor action of ANG II, indicating an enhanced response to AT1 receptor stimulation (15, 17). We asked the question whether absence of AT2 receptor transcription could result in alterations in AT1 receptor binding or mRNA expression in selected areas of the kidney in this mouse model.
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MATERIALS AND METHODS |
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Animals.
Mice were obtained form the Department of Biochemistry, Nashville
University, and were kept under controlled conditions with free access
to water and food, according to protocols approved by National
Institute of Mental Health (NIMH) Animal Care and Use Committee. We
produced the agtr2 gene-disrupted mice by the injection of
agtr2 disrupted embryonic stem cells (E14-1) from the
129 Ola mouse line into blastocyts derived from C57BL/6 mice, as
described previously (17). After the genotype of
F2 heterozygous females (agtr2 /+) was clearly
confirmed, they were backcrossed with C57BL/6 wild-type males for three
generations. Littermate gene-disrupted (agtr2
/Y) and
control wild-type (agtr2 +/Y) males were selected from the
third backcross progeny to minimize the effect of differences in
genetic background.
ANG II receptor binding. Sar1-ANG II (Peninsula Laboratories, Belmont, CA) and CGP-42112 (Neosystems Laboratory, Strasbourg, France) were iodinated by New England Nuclear (Boston, MA) to a specific activity of 2,200 Ci/mmol.
Adjacent kidney sections were preincubated for 15 min at 22°C in 10-mM sodium phosphate buffer, pH 7.4, containing 120 mM NaCl, 5 mM EDTA, 0.005% bacitracin (Sigma, St. Louis, MO), and 0.2% protease-free BSA (Sigma), followed by incubation for 2 h at 22°C in fresh buffer, prepared as above with the addition of 50 µM Plummer's inhibitor (Calbiochem, La Jolla, CA), 100 µM phenylmethylsulfonyl fluoride (Sigma), 500 µM phenantrolin (Sigma), and 0.5 nM [125I]Sar1-ANG II. After an incubation for 120 min at 22°C the sections were washed four times for 1 min each in ice-cold 50 mM Tris-HCl buffer (pH 7.4), followed by a 30 s wash in ice-cold water, and dried under a stream of cold air. Binding of [125I]Sar1-ANG II to AT1 receptors was determined in adjacent kidney sections as follows. Some sections were incubated with 0.5 nM [125I]Sar1-ANG II to determine total binding. Adjacent sections were incubated as above with the addition of 10Quantitative receptor autoradiography. We exposed dry sections to Hyperfilm-3H (Amersham, Arlington Heights, IL) along with 16-µm sections of autoradiographic 125I microscales (Amersham) at 4°C. Films were developed in ice-cold D-19 developer (Eastman Kodak, Rochester, NY) for 4 min, fixed in Kodak rapid fixer for 4 min at 22°C, and rinsed in water for 15 min. We measured optical densities in the autoradiograms by computerized microdensitometry by using the NIH Image 1.6 analysis system (NIMH, Bethesda, MD). For quantitative autoradiography, we measured the optical densities separately in kidney glomeruli, the rest of the cortex, and outer and inner stripes of the outer medulla. The optical densities were related to the concentration of radioactivity present in the sections by comparison with the 125I microscales, and transformed to corresponding values of fmol/mg protein (37). These values should be considered as arbitrary units, because the ligand concentrations used are below saturation, and because the actual protein-tissue-protein concentration varies between the different regions of the kidney (37). We found similar differences between groups when values were calculated as optical densities before comparison to 125I standards.
In situ hybridization histochemistry. In situ hybridization was performed by using 35S-labeled antisense and sense (control) riboprobes (21). A 478-bp EcoR I/SacI cDNA fragment of rat AT1A receptor (19, 39) showing 95 and 88% sequence homology to the mouse AT1A and AT1B receptor cDNA, respectively, and 99.4 and 92.5% amino acid homology to mouse AT1A and AT1B receptors, respectively (19, 39), was subcloned into the pBluescript II KS+ vector. Riboprobes were labeled by in vitro transcription by using an RNA labeling kit (Amersham). Because we used a riboprobe to the coding region of the rat AT1 receptor that has a very high homology between AT1A and AT1B-rodent subtypes, we did not determine the relative contribution of kidney AT1A or AT1B receptor subtypes in our experiments. However, over 95% of the renal AT1 receptors are of the AT1A subtype (22). Thus the mRNA data presented here predominantly reflects the regulation of the AT1A receptors.
Sections were fixed in 4% paraformaldehyde for 10 min, acetylated for 10 min in 0.1 M triethanolamine HCl, pH 8.0, containing 0.25% acetic anhydride, dehydrated in alcohols, and air dried. Each section was covered with 50-µl hybridization buffer containing 50% formamide, 0.3 M NaCl, 2 mM EDTA, 20 mM Tris, pH 8.0, 1 × Denhardt's solution, 10% dextran sulfate, 100 µg/ml salmon sperm DNA, 250 µg/ml yeast tRNA, 150 mM DTT, 0.1% SDS, and 40,000-counts per minute/µl sense or antisense probe. Sections were hybridized overnight at 54°C, treated with 40 µg/ml RNase A (Sigma, St. Louis, MO) for 30 min, and washed in sodium chloride/sodium citrate (SSC) with increasing stringency. After a final wash in 0.1 × SSC at 65°C for 60 min, sections were dehydrated through alcohols and exposed to Hyperfilm-3H (Amersham) along with 14C microscales (Amersham) for 7 days. Films were developed as described above. The intensities of hybridization signals in kidney glomeruli, the rest of the cortex, and outer and inner stripes of the outer medulla, were quantified as nCi/g tissue equivalent by measuring optical film densities by using the NIH Image 1.61 program. Data were calibrated with 14C microscales after subtraction of the values obtained in the same areas of adjacent sections hybridized with sense (control) probes (nonspecific hybridization). The values obtained represent arbitrary units, because the protein content or weight of the different kidney areas may be different (32). We found similar differences between groups when values were calculated as optical densities before comparison to 14C standards. For cellular localization, slides were dipped in Kodak NTB2 photo emulsion, exposed for 4 wk, developed in Kodak D-19 developer for 3 min at 15°C, fixed for 4 min, and counterstained with hematoxylin and eosin (Fisher Scientific, Fair Lawn, NJ).Statistical analysis. Results were expressed as means ± SE, calculated and analyzed by using GraphPad Prism (version 2.00) and Microsoft Excel (version 7.0a). Statistical analysis for values obtained from the displacement studies by using single concentrations of the displacers was performed by using a one-way ANOVA followed by post hoc analysis with the Newman-Keuls multiple comparison test. Mean ± SE values of wild-type and AT2 gene-disrupted mice were compared for significance by using unpaired Student's t-test.
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RESULTS |
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ANG II receptor subtype expression and mRNA in wild-type mice.
We studied ANG II receptor subtype binding and mRNA in the kidney of
male wild-type and AT2 gene-disrupted mice. Binding to AT1 receptors was, as expected, high and selectively
localized in the kidney of wild-type mice. In wild-type mice, the
highest levels of losartan-sensitive, PD-123319-insensitive,
[125I]Sar1-ANG II binding to AT1
receptors were present on glomeruli (Fig. 1, A-E) and lower
levels in the inner stripe of the outer medulla (Table
1). Binding to AT1 receptors
was also present in the rest of the cortex and the outer stripe of the
outer medulla (Table 1).
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ANG II AT1 receptor expression and mRNA in AT2 gene-disrupted mice. As expected, the AT2 receptor gene-disrupted male did not express losartan-insensitive, PD-123319-sensitive (AT2) [125I]Sar1-ANG II binding sites (Fig. 1, F-J) or AT2 receptor-selective [125I]CGP-42112 binding (Fig. 4, E-H) in the renal cortex or in other areas of the kidney.
A remarkable difference in ANG II AT1 receptor binding studied with quantitative autoradiography, and mRNA, as determined by in situ hybridization, was noted in AT2 gene-disrupted mice compared with wild-type controls. In AT2 receptor gene-disrupted mice, both [125I]Sar1-ANG II binding to AT1 receptors and AT1 receptor mRNA were higher compared with values in wild-type mice. Significant increases in AT1 receptor binding (~125%) (Table 1, Fig. 1, G and J) and AT1 mRNA (~50%) (Table 1, Fig. 3, B and C) were found in glomeruli. Binding was significantly increased in the rest of the renal cortex (3-fold) and in the outer stripe of the outer medulla (~90%). In these areas there was a tendency toward increased expression of AT1 mRNA, a ~45% increase in the rest of the renal cortex, and about a ~55% increase in the outer stripe of the outer medulla (Table 1). In the rest of the renal cortex and the outer stripe of the outer medulla of AT2 gene-disrupted mice, AT1 receptor expression was also significantly higher (Table 1). In these areas there was increased expression of AT1 mRNA, but the results did not achieve statistical significance (Table 1). Conversely, no significant differences were found in AT1 receptor binding or mRNA in the inner stripe of the outer medulla between wild-type animals and AT2 gene-deficient male mice (Table 1). ![]() |
DISCUSSION |
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We report that gene disruption of the ANG II AT2 receptor results in marked and selective alterations on the protein and mRNA expression of the renal AT1 receptors in the male mouse.
First, we analyzed the distribution of AT1 receptor binding and mRNA in the kidney of wild-type male mice. The highest numbers of AT1 receptors and highest AT1 mRNA expression occur in the glomeruli, significant AT1 receptor binding, and mRNA in the inner stripe of the outer medulla, and lower binding and receptor mRNA in the rest of the kidney cortex. These results are in agreement with previous data from other mammalian species and with the demonstration of AT1 receptors, not only in glomeruli but also in proximal and distal tubules, medullar interstitial cells, and the vasculature (1, 4, 6-10, 22, 23, 30, 36, 38, 40, 48). In addition, we detected low levels of AT1 receptor binding, and significant levels of AT1 receptor mRNA, in the outer stripe of the outer medulla of wild-type mice. This indicates that some AT1 receptors may be located, in the mouse, in medullar structures that do not express AT1 receptors in the rat (47).
We found a clear expression of AT2 receptor binding in the kidney of the wild-type mice, a finding that again contrasts with the reported absence of AT2 receptors in adult rats (1, 4, 5). The number of AT2 receptors in the adult mouse kidney was much lower than that of AT1 receptors, and followed a different pattern of localization. AT2 receptor binding was restricted to very selective cortical areas associated with renal vessels. This is in agreement with the reported localization of AT2 receptors in renal vessels of other species, including humans (8, 9, 10, 30, 48). Under the conditions of our assay, we could not find AT2 receptor binding in kidney glomeruli and interstitial cells, as proposed with immunocytochemical techniques (38). If present, these receptors might be expressed in low amounts below the sensitivity of our assay.
Thus our analysis of ANG II receptor subtypes in the adult mice indicated that both receptors were clearly expressed, that the AT1 receptor predominated, and that the localization of the receptor subtypes occurred, at least for the most part, with exception of the vasculature, in separate renal structures.
Next, we studied ANG II receptor subtype expression and mRNA in AT2 gene-disrupted mice. In the kidney of adult AT2 gene-disrupted mice there was no PD-123319-sensitive, losartan-insensitive binding and no [125I]CGP 42112, AT2-selective binding. The total absence of AT2 receptor binding in the AT2 gene-disrupted mouse was expected, because AT2 receptors are encoded by a single gene (16, 19, 39), and confirmed the identity of AT2 receptor binding sites with the cloned AT2 receptor.
The main finding in our study was the demonstration of a significant increase in AT1 receptor expression and mRNA in the kidney of adult AT2 gene-disrupted mice. Ours is a clear example of how the gene disruption of one receptor can alter the expression of another receptor. This is particularly remarkable considering that the expression of renal AT2 receptors in wild-type mice is very low, compared with that of AT1 receptors. Our results further support the hypothesis that the level of expression of the AT2 receptors inversely correlates with that of AT1 receptors. Earlier studies demonstrated that the cardiac specific over-expression of AT2 receptors attenuates the AT1-mediated pressor and chronotropic effects of ANG II (29). In addition, AT2 receptors are highly expressed in the fetal kidney, and their numbers decrease during gestation in parallel with a concomitant increase in AT1 receptor expression (4).
Activation of AT1 and AT2 receptors in wild-type animals results in effects different, and in most cases opposite; and stimulation of AT2 receptors was postulated to limit the response of AT1 receptors to ANG II (17). Stimulation of kidney AT1 receptors decreases cortical and medullar blood flow and decreases urine flow and natriuresis, the principal renal effects of ANG II, shifting pressure natriuresis to the right (11). Conversely, in wild-type animals, stimulation of AT2 receptors was reported to increase pressure natriuresis (26) and their stimulation results in renal vasodilatation, probably as a consequence of production of cGMP, (42), nitric oxide (43), and prostaglandin F2 alpha (44), and increased arachidonic acid release (20). AT1 receptor blockade produces vasodilatation, diuresis and natriuresis, and this was proposed to be due to unopposed AT2 receptor stimulation (3, 33, 35, 42). The evidence of a physiological role of renal AT2 receptors, however, is controversial. AT2 receptor blockade was reported to potentiate the ANG II-induced PGE2 production after AT1 receptor stimulation (42) and prevents the effect of ANG II on the vasculature (24). However, other studies indicate that chronic blockade of AT2 receptors in wild-type adult animals does not alter the response to AT1 receptor stimulation by ANG II (33).
In mice lacking AT2 receptor expression there is increased sodium retention, rightward shift in pressure natriuresis and diuresis, reduction in cortical and medullar blood flow, increased blood pressure, and enhanced hypertensive response to ANG II administration (12, 15, 17). The phenotype of the AT2 receptor gene-disrupted mouse may be related to the upregulation of the AT1 receptor, rather than negatively reflecting the actions of the AT2 receptor (12, 45). It is also possible that the AT2 receptor gene-disrupted phenotype could be the result of a lost balance between AT1 and AT2 receptors, with a shift toward predominance of AT1-related effects. In addition, higher AT1 receptor transcription and expression could explain the enhanced fibrosis after ureteral occlusion in AT2 gene-deficient mice (25, 28), because kidney fibrosis induced by ANG II is AT1 receptor dependent (27).
There is a recent report (12) of increased AT1 receptor mRNA in the whole kidney of AT2 gene-disrupted mice. Our findings of increased AT1 receptor binding indicate that an actual increase in AT1 receptor expression occurs in AT2 receptor gene-disrupted mice. In addition we demonstrate here that upregulation of renal AT1 receptors predominantly occurs in cortical structures, the kidney glomeruli, and probably in the tubular epithelium, and in the outer stripe of the outer medulla. In AT2 receptor gene-disrupted mice, there are no changes in AT1 receptor expression in the inner stripe of the outer medulla. Thus the AT1 upregulation and the AT2-AT1 feedback in this model are structure and cell specific. Although the expression of glomerular and cortical interstitial AT1 receptors may depend on AT2 receptor expression, the AT1 receptor expression in the inner stripe of the outer medulla does not. We conclude from our results that AT1 receptors in renal glomeruli, interstitial, and medullar cells are differentially regulated.
Last, our findings further support the hypothesis of a crosstalk or feedback between AT1 and AT2 receptor subtypes. It appears that AT1 receptors for the most part do not coexist with AT2 receptors in the same renal cells. For this reason, the mechanism of feedback is probably indirect, through modifications in kidney function related to the absence of AT2 receptors, and the upregulation of renal AT1 receptors.
In our model, when alterations in the transcription and expression of AT2 receptors are present from birth, renal AT1 receptor expression and consequently renal function, are profoundly affected in the adult. Because AT1 receptor antagonists are widely used in the treatment of cardiovascular disease, the crosstalk/feedback between AT1 and AT2 receptors has significant pathophysiological and clinical relevance.
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ACKNOWLEDGEMENTS |
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W. Haüser was supported by a grant from ASTRA GmbH, Germany.
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FOOTNOTES |
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Address for reprint requests and other correspondence: J. M. Saavedra, Section on Pharmacology, National Institute of Mental Health, Center Dr. MSC 1514, Bldg. 10, Rm. 2D-57, Bethesda, MD 20892 (E-mail: Saavedrj{at}irp.nimh.nih.gov).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 5 April 2000; accepted in final form 29 September 2000.
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