Published online before print March 17, 2003, doi: 10.1161/01.HYP.0000062466.38314.B7
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(Hypertension. 2003;41:984.)
© 2003 American Heart Association, Inc.
Scientific Contributions |
Differential Expression of AT1 Receptors in the Pituitary and Adrenal Gland of SHR and WKY
From the Institute of Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Lübeck, Germany.
Correspondence to Olaf Jöhren, PhD, Institute of Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Ratzeburger Allee 160, D-23538 Lübeck, Germany. E-mail Joehren{at}medinf.mu-luebeck.de
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Abstract |
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The renin-angiotensin (ANG) system has been implicated in the development of hypertension in spontaneously hypertensive rats (SHR). Because SHR are more susceptible to stress than normotensive Wistar-Kyoto rats (WKY), we measured the mRNA expression of AT1A, AT1B, and AT2 receptors in the hypothalamo-pituitary-adrenal (stress) axis of male SHR in comparison to age-matched WKY at prehypertensive (3 to 4 weeks), developing (7 to 8 weeks), and established (12 to 13 weeks) stages of hypertension. AT1A receptor mRNA was mainly expressed in the hypothalamus and adrenal gland. AT1B receptor mRNA was detected in the pituitary and adrenal gland. AT2 receptor mRNA was prominent only in the adrenal gland. When compared with WKY, SHR showed increased AT1A receptor mRNA levels in the pituitary gland at all ages in contrast to reduced pituitary AT1B receptor mRNA levels. In the adrenal gland of SHR, AT1B receptor mRNA levels were decreased at the hypertensive stages when compared with WKY. The reduced expression of adrenal AT1B receptor mRNA was localized selectively in the zona glomerulosa by in situ hybridization. No differences were observed between WKY and SHR in the expression of hypothalamic ANG receptors. ANG significantly increased plasma levels of adrenocorticotropic hormone (ACTH) and corticosterone in dexamethasone-treated SHR but not in WKY. The aldosterone response to ANG was similar in SHR and WKY. Our results suggest a differential gene expression of AT1A and AT1B receptors in the hypothalamo-pituitary-adrenal axis of SHR and normotensive WKY and imply the participation of AT1 receptors in an exaggerated endocrine stress response of SHR to ANG.
Key Words: receptors, angiotensin • rats, spontaneously hypertensive • pituitary gland • adrenal gland
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Introduction |
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Angiotensin II (ANG), the main active peptide of the renin-angiotensin system, acts at 2 distinct receptor subtypes, namely type 1 (AT1) and type 2 (AT2) receptors. The role of AT1 receptors in the regulation of cardiovascular functions, fluid homeostasis, and hormone release is well established, and several AT1 receptor antagonists are used for the treatment of hypertension.1 In rodents, 2 pharmacologically similar AT1 receptor isoforms, AT1A and AT1B, exist, which are encoded by 2 distinct genes and are expressed and regulated differentially.2–5 High levels of AT1A receptor mRNA are present in the rodent brain, kidney, and vasculature, whereas AT1B receptor mRNA is mainly expressed in the pituitary and adrenal glands.6–10 Although widely expressed in fetal and young rats,11 in adult rats, the expression of AT2 receptors is low and restricted to certain organs, such as the brain and adrenal gland.1,12 The expression of all ANG receptor subtypes in the hypothalamo-pituitary-adrenal (HPA) axis, which is activated in response to stress, as well as the regulation of ANG receptors by restraint stress13–15 implies important roles of the ANG system in the regulation of the activity of the HPA axis. Accordingly, ANG has been shown to regulate corticotropin-releasing factor, adrenocorticotropic hormone (ACTH), and corticosterone synthesis and secretion.16–18
Spontaneously hypertensive rats (SHR) show an impaired response and habituation to various forms of stress such as immobilization and exposure to heat or open field, and they differ in their neuroendocrine reaction to stress from normotensive Wistar-Kyoto rats (WKY).19–23 The ANG system has been implicated in the impaired stress response of SHR.24–27 There are several studies showing differences in the numbers of binding sites for radiolabeled ANG between SHR and WKY in the kidney, vasculature, heart, pituitary, adrenal gland, and brain, including the hypothalamus and neuronal cultures.28–32 Because AT1A and AT1B receptors are pharmacologically indistinguishable, the distinct expression of these AT1 receptor isoforms was not addressed in these studies. Using a different approach, Iwai et al33 could not detect differences of AT1A mRNA levels in the brain and adrenal gland between WKY and SHR, whereas Raizada et al34 found increased AT1A and AT1B receptor mRNA levels in the hypothalamus of SHR compared with WKY. Furthermore, AT1B receptor mRNA appeared to be upregulated in the heart ventricle of SHR.2 Nevertheless, thus far, no information is available regarding the gene expression of AT1A and AT1B receptor subtypes in the pituitary and of AT1B receptors in the adrenal gland of SHR in comparison to WKY. Therefore, we analyzed the mRNA expression of AT1A, AT1B, and AT2 receptor subtypes in the hypothalamus, pituitary, and adrenal gland of SHR at different developmental stages of hypertension in comparison with age-matched normotensive WKY.
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Methods |
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Animals and Treatments
Male SHR and age-matched WKY at 3 different postnatal ages corresponding to the prehypertensive (3 to 4 weeks), developing (7 to 8 weeks), and established (12 to 13 weeks) stages of hypertension were purchased from Charles-River. Rats were kept under controlled conditions with a 12 hour/12 hour dark/light cycle and ad libitum access to standard diet and water. For RNA analysis, rats were anesthetized with pentobarbital (50 mg/kg IP) and killed by decapitation. Tissues were removed immediately, frozen in isopentane (-30°C), and stored at -80°C until use.
To measure the effect of ANG on adrenal hormones, 12-week-old male SHR and WKY were treated with a single intraperitoneal injection of dexamethasone (100 µg) to suppress ANG-induced ACTH release.35 Three hours after injection, rats were anesthetized with 100 mg/kg IP methohexital, and the right femoral artery was catheterized. Anesthesia was continued with 5 mg IA pentobarbital; 1 or 10 µg ANG was infused over a period of 30 minutes, and 500 µL blood was withdrawn for hormone assays. All animal protocols complied with the National Institutes of Health (NIH) Guide for the Care and Use of Laboratory Animals and were approved by the Ministerium für Umwelt, Natur und Forsten of Schleswig-Holstein, Germany (animal protocol 9/A37/01).
RNA Isolation and cDNA Synthesis
Hypothalami were dissected according to Palkovits and Brownstein.36 The brains were adapted to -10°C, and coronal cuts were made at 900 µm (at the optic chiasm) and 4800 µm (just posterior of the mamillary nucleus) posterior of the bregma. The hypothalamic slice was turned on its posterior surface and cut laterally directly before the amygdala and dorsally just underneath the anterior commissure.
Hypothalami and pituitary and adrenal glands were homogenized in the presence of guanidinium isothiocyanate. Total RNA was isolated with the use of silica gel–based spin columns and treated with DNase I (RNeasy Kit, Qiagen GmbH). First-strand cDNA was synthesized from 1 µg total RNA in a volume of 20 µL containing 5 mmol/L MgCl2, 10 mmol/L Tris-HCl, pH 9.0, 50 mmol/L KCl, 0.1% Triton X-100, 1 mmol/L dNTPs, 1 U/µL RNasin, 0.5 µg oligo-(dT)15 primer, and 15 U AMV reverse transcriptase (Promega GmbH). By performing PCR in control samples in which the reverse transcriptase was omitted, possible contamination with genomic DNA was monitored. As a control for RNA integrity and successful cDNA synthesis, the ß-actin mRNA expression of each sample was analyzed by RT-PCR.
Semiquantitative PCR
AT1 receptor primers spanning identical regions of the AT1A and AT1B receptor cDNA were used.3,37 According to Ruan et al,38 the amplified AT1A and AT1B receptor cDNA was identified by restriction with EcoR I (Figure 1A). AT2 receptor and ß-actin specific sense and antisense primers were designed on the basis of the published cDNA sequences.39,40 All primers (Table) were constructed with the use of Primer3 software by S. Rozen and H.J. Skaletsky (http://www-genome.wi.mit.edu/genome_software/other/primer3.html) and were obtained from Live Technologies GmbH (Karlsruhe, Germany).
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PCR was performed as described previously.41 Five microliters of first-strand cDNA was incubated in the presence of 10 mmol/L Tris-HCl, pH 9.0, 50 mmol/L KCl, 0.1% Triton X-100, 1.5 mmol/L MgCl2, 0.2 mmol/L dNTPs, 0.5 nmol/L sense and antisense primers, and 1.2 U DNA Polymerase (DyNAzyme II, Biometra GmbH) in a final volume of 50 µL. The PCR conditions were 28 to 32 cycles of denaturation for 1 minute at 95°C, annealing for 30 seconds at 56°C, and extension for 60 seconds at 72°C. The specificity of the amplified AT1A and AT1B receptors cDNA was confirmed by restriction with Alu I, which cuts the AT1A receptor cDNA to 20, 54, 83, and 154 bp fragments and the AT1B receptor cDNA to 103-bp and 208-bp fragments (Figure 1A). EcoR I selectively cuts the AT1A receptor cDNA to 128- and 183-bp fragments and leaves the AT1B receptor cDNA intact (Figure 1A). AT2 receptor cDNA was restricted with Ssp I to 26-, 92-, and 131-bp fragments.
For semiquantitative analysis of AT1 and AT2 receptor mRNA levels, agarose gels were digitized and analyzed densitometrically with Scion Image for Windows (Scion Co), which is based on the public domain NIH Image program (developed at the US National Institutes of Health and available on the Internet at http://rsb.info.nih.gov/nih-image). To ensure amplification within the exponential phase of the PCR, the PCR cycle numbers used for AT1A, AT1B, and AT2 receptor and ß-actin cDNA amplification were optimized for each primer pair and tissue by kinetic analysis (22 to 40 cycles). Depending on the primers and tissues, cycle numbers between 28 and 32 were found to produce exponential amplification of PCR products. The mRNA levels of ß-actin were used as internal standard to normalize AT1 and AT2 receptor mRNA levels.41
cDNA Cloning and In Vitro Transcription of Riboprobes
Adrenal cDNA was amplified by PCR with the following AT1B receptor specific primers, which amplify a part of the 3'-noncoding region without significant homology to the AT1A receptor cDNA: sense primer 5'-GTGGAGTGAGAGGGTTCAA-3' and antisense primer 5'-GACATTATTCAGGCAAGCTG-3', spanning nucleotides 1268 to 1896 of the published AT1B receptor cDNA.3 The amplified AT1B receptor cDNA was subcloned into the pCR-II Vector with the use of a TA-cloning kit (Invitrogen), and its identity was confirmed by nucleotide sequencing (MWG Biotech).
AT1B receptor–specific antisense and sense (control) RNA probes were labeled by in vitro transcription in the presence of 200 µCi of [35S]UTP (800 Ci/mmol, Amersham-Pharmacia), 0.5 µg of the linearized plasmid, and T3 or T7 RNA polymerase. Labeled RNA-probes were separated from unincorporated [35S]UTP by centrifugation through Sephadex G-50 microcolumns (Amersham-Pharmacia).
In Situ Hybridization Histochemistry
In situ hybridization was performed as described earlier.42 Adrenal glands from SHR and WKY were sectioned at -20°C in a cryostat, and 20-µm sections were thaw-mounted alongside on aminoalkylsilane-coated glass slides (Sigma). After fixation in 4% paraformaldehyde for 10 minutes, sections were dehydrated in ethanol and air-dried. Hybridization was performed with 1 to 2 pmol/mL labeled RNA-probes in buffer containing 50% formamide, 10% dextran sulfate, 1xDenhardt’s solution, 20 mmol/L Tris (pH 7.5), 0.3 mol/L NaCl, 1 mmol/L EDTA, 150 mmol/L dithiothreitol, 0.2% sodium dodecyl sulfate, 100 µg/mL salmon sperm DNA, and 250 µg/mL yeast tRNA for 18 hours at 54°C. Subsequently, sections were treated with RNAse A, washed in NaCl-Na citrate (SSC) buffer to a final stringency of 0.1xSSC at 60°C, dehydrated in ethanol, and exposed to Hyperfilm H3 (Amersham-Pharmacia) along with C-14 standards (American Radiolabeled Chemicals, Inc). Films were analyzed densitometrically with Scion Image.42
Radioimmunassays
Plasma concentrations of ACTH, corticosterone, and aldosterone were measured with the use of 125I radioimmunoassay kits (ICN Biomedicals). For aldosterone detection, 100 µL serum was extracted twice with 2 mL ethyl acetate/hexane (3:2), evaporated, and reconstituted in 1 mL RIA buffer; 250 µL was used in the assay. For corticosterone detection, 100 µL serum was diluted 1:200 with RIA buffer and 100 µL thereof was used in the assay. For ACTH detection, 100 µL serum was used without dilution. All samples were assayed in duplicate according to the manufacturers instructions. Intra-assay and interassay variations were <6% and 10%, respectively.
Statistics
Data are presented as mean±SEM. Effects of age and genetic groups were estimated by 2-way ANOVA, with the use of GraphPad Prism Software (GraphPad Software Inc). Effects of ANG on plasma hormones were analyzed by 1-way ANOVA. For subsequent group comparisons the Bonferroni posttest was used. Probability values <0.05 were considered statistically significant.
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Specific Amplification of ANG Receptor Subtypes
RT-PCR with AT1 receptor–specific and AT2 receptor–specific sense and antisense primers resulted in the amplification of distinct cDNA fragments of the expected size of 311 bp and 249 bp, respectively (Figure 1). Restriction analysis of the amplified AT1 and AT2 receptor cDNA confirmed the specificity of our PCR showing the restriction fragments as predicted according to the published cDNA sequences (Figure 1). Restriction with EcoR I, which selectively cuts AT1A but not AT1B receptor cDNA, allowed the differentiation between these 2 AT1 receptor isoforms (Figure 2). In samples in which the RT was omitted and in water control reactions, no amplification products were observed after PCR. The integrity of the cDNA was confirmed by analysis of ß-actin mRNA.
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Distribution of ANG Receptor Subtypes in the HPA Axis
In normotensive WKY, AT1A receptor mRNA was mainly expressed in the hypothalamus and adrenal glands and was very low in the pituitary gland, whereas AT1B receptor mRNA was primarily found in the pituitary and adrenal glands (Figure 2). AT2 receptor mRNA was highly expressed in the adrenal glands and at lower levels in the hypothalamus (Figure 3). No AT2 receptor mRNA was detected in the pituitary gland.
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Expression of ANG Receptor Subtypes in WKY and SHR
In the hypothalamus, no differences were detected in AT1A, AT1B, or AT2 receptor mRNA levels between SHR and WKY at different postnatal ages corresponding to the prehypertensive (3 to 4 weeks old), developing (7 to 8 weeks old), and established (12 to 13 weeks old) stages of hypertension, although there was a tendency of lower AT1A and AT1B receptor mRNA in prehypertensive SHR (Figure 4). In the pituitary gland, we detected significantly higher levels of AT1A receptor mRNA and significantly lower levels of AT1B receptor mRNA at all postnatal ages (Figure 5). In the adrenal gland, AT1B receptor mRNA levels were significantly reduced in 7- to 8- and 12- to 13-week-old SHR when compared with WKY (Figure 6). Adrenal AT2 receptor mRNA levels were high in 3- to 4-week-old rats and declined to some extent with age (Figure 6). No significant differences were found in adrenal AT1A or AT2 receptor mRNA levels between SHR and WKY at the different ages (Figure 6). On the whole, there was a tendency of reduced AT2 receptor mRNA levels in the adrenal of SHR.
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Localization of AT1B Receptor mRNA in the Adrenal Gland of WKY and SHR
The AT1B receptor mRNA expression in the adrenal gland of WKY and SHR was localized exclusively in the zona glomerulosa by in situ hybridization with specific AT1B receptor antisense RNA probes (Figure 7). Hybridization with control sense RNA probes resulted in a very low background signal (not shown). Semiquantitative analysis demonstrated reduced AT1B receptor mRNA levels in the zona glomerulosa of 12- to 13-week-old but not in 7- to 8-week-old SHR when compared with WKY (Figure 7).
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Effect of ANG on Plasma Hormones in Dexamethasone-Treated WKY and SHR
Infusion of a low dose of ANG (1 µg) over a period of 30 minutes had no effect on plasma levels of ACTH, corticosterone, and aldosterone in dexamethasone-treated WKY or SHR (Figure 8). However, a high dose of ANG (10 µg) significantly increased plasma levels of ACTH and corticosterone in dexamethasone-treated SHR but not in dexamethasone-treated WKY (Figures 8A and 8B). Plasma levels of aldosterone were equally increased in both WKY and SHR after infusion of 10 µg ANG (Figure 8C).
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Discussion |
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The current results demonstrate for the first time the differential mRNA expression of AT1A and AT1B receptors in the pituitary and adrenal glands of SHR compared with WKY. The changes in pituitary and adrenal mRNA levels of AT1A and AT1B receptors in SHR are accompanied by an increased responsiveness of the HPA axis to ANG in dexamethasone-suppressed animals.
ANG regulates blood pressure by regulating the vascular tone and fluid homeostasis, which are controlled by the stimulation of aldosterone, norepinephrine, and vasopressin release, effects mediated by AT1 receptors.1,43,44 Little is known about the relative physiological roles of the 2 AT1 receptor isoforms that are found in rodents. Recent results in AT1A and AT1B receptor-deficient mice have shown the involvement of central AT1A receptors in the regulation of blood pressure and fluid homeostasis and that of central AT1B receptors in drinking behavior.45,46 Because AT1A and AT1B receptors cannot be distinguished pharmacologically or by immunohistochemistry, we assessed the mRNA expression of these AT1 receptor isoforms by semiquantitative RT-PCR combined with receptor isoform-specific restriction of the PCR products.38 Using this method, we confirmed the tissue-specific distribution of AT1A, AT1B, and AT2 receptor mRNA and their high expression in the HPA axis.6–10
In the pituitary gland of SHR, we found AT1A receptor mRNA levels notably increased compared with WKY, whereas AT1B receptor mRNA levels were decreased, and these differences were evident at a young age, before the onset of hypertension. Reduced ANG binding sites in the anterior pituitary of SHR as described earlier47 may reflect this decrease in AT1B receptor expression. However, since in normotensive adult rats pituitary AT1A receptor mRNA levels are usually very low or undetectable,8,10,48 the significant mRNA expression of pituitary AT1A receptors in adult SHR in the current study also suggests specific ANG-related functional changes of the pituitary gland in SHR. Although AT1B receptors appear to be mainly expressed in prolactin-producing pituitary cells and to a lower degree in ACTH-producing cells,48 the pituitary cells expressing AT1A receptors were not identified thus far, and considerations about possible functions of pituitary AT1A receptors in SHR are only speculative at this point. ANG was shown to directly affect pituitary prolactin, ACTH, and growth hormone release,49–51 and these effects appear to be mediated differentially by AT1A and AT1B receptors. For example, ANG may directly stimulate prolactin release from the pituitary gland by acting on AT1B receptors and inhibit pituitary prolactin indirectly by stimulating dopamine release through central AT1A receptors.42 Earlier studies on the pituitary hormonal system revealed higher basal prolactin in SHR19 and enhanced growth hormone but not prolactin secretion from pituitary cells after ANG in SHR.52 Thus, reduced pituitary mRNA levels of AT1B receptors in SHR may reflect adaptive changes to high prolactin levels caused by other secretagogues. We found elevated plasma levels of ACTH and corticosterone in response to ANG in dexamethasone-treated SHR but not in dexamethasone-treated WKY. Since this increased responsiveness to ANG is associated with an increased mRNA expression of AT1A receptors and a decreased mRNA expression of AT1B receptors in the pituitary, the pituitary AT1A receptor may account for the ANG-induced elevation of plasma ACTH and a consequent increase of plasma corticosterone in SHR. Interestingly, restraint stress results in a similar shift of pituitary AT1A and AT1B receptor expression.15 Thus, the increased pituitary AT1A receptors may make SHR more susceptible to stress. However, the detailed physiological role of the pituitary AT1A receptors in SHR remains unclear and awaits further clarification.
One of the main AT1 receptor–mediated effects of ANG is the stimulation of aldosterone release from the adrenal gland.43 The finding that the aldosterone response to sodium depletion is not influenced in AT1A receptor–deficient mice suggests a major role of the AT1B receptor.53 Indeed, although AT1A receptors are present in all cortical layers and the medulla of the adrenal gland,9 we found AT1B receptor mRNA highly and specifically expressed in the zona glomerulosa, in accordance with earlier studies.8,9 Furthermore, we show that the reduced adrenal AT1B receptor mRNA levels in SHR are localized exclusively in the aldosterone-producing zona glomerulosa. Thus, our data suggested an impaired aldosterone response to ANG in SHR. However, in dexamethasone-treated WKY and SHR, we found a similar increase of plasma aldosterone after ANG treatment. Since plasma aldosterone levels appear to be increased in SHR,19 reduced AT1B receptor mRNA levels may reflect adaptive changes to reduce aldosterone release and to protect from excess aldosterone. On the other hand, changes in AT1B receptor mRNA levels may not translate to changes in protein levels. The dose of dexamethasone we used was shown to efficiently suppress ANG-dependent ACTH release in normotensive Sprague-Dawley rats.35 In contrast to dexamethasone-treated WKY, ANG still increased ACTH in dexamethasone-treated SHR. Thus in SHR, ANG-induced ACTH release may also contribute to the aldosterone release. We found no differences in the mRNA levels of adrenal AT2 receptors between WKY and SHR. The decrease of adrenal AT2 receptor mRNA levels with increasing age is in line with earlier observations in adrenals and many other tissues.1
In the hypothalamus, we did not find differences in AT1 receptor mRNA levels between SHR and WKY despite previous findings of an increase of AT1 receptor mRNA in the hypothalamus and brain stem of SHR compared with WKY.34 However, our findings correspond to previous results showing that ANG binding sites were unaffected in various hypothalamic and brain stem nuclei of SHR, except for the spinal trigeminal nucleus, when compared with WKY.30 Hence, differences in AT1 receptor mRNA might be restricted to distinct brain nuclei and therefore not accessible by our method. Nevertheless, we found significant differences in the mRNA expression of AT1A and AT1B receptors in the pituitary and adrenal gland of SHR compared with WKY. These differences occurred before the onset of hypertension and in the phase of developing high blood pressure. Thus, a causal role between an exaggerated stress response and an altered expression of pituitary and adrenal AT1 receptors may exist. This correlation is further supported by our findings in SHR of an enhanced activity of the HPA axis in response to ANG. Interestingly, the regulation of pituitary and adrenal AT1A and AT1B receptor mRNA in SHR, as described in our current study, shows similarities with the increased pituitary AT1A receptor and decreased pituitary and adrenal AT1B receptor expression found in rats after immobilization stress.15 Our data suggest that the known susceptibility of SHR to stress is linked to the differential expression of pituitary and adrenal AT1A and AT1B receptors and support an important role of the ANG system in the regulation of the stress response in SHR.
Perspectives
In humans, enhanced stress reactivity may be involved in combination with other environmental and genetic factors in the development of hypertension.54 In contrast to rodents, a single gene encodes the human AT1 receptor.55 However, several splicing variants of the human AT1 receptor exist that are not only expressed differentially but are functionally different.56,57 Since the physiological response of AT1 receptors to ANG is very similar in humans and rodents, a better understanding of divergent regulations and functions of AT1 receptor isoforms in rodents may help to elucidate the involvement of AT1 receptor isoforms in the development of stress-related disorders in humans, including hypertension.
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Acknowledgments |
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The authors thank Klaus Tempel and Gudrun Vierke for expert technical assistance.
Received December 30, 2002; first decision January 23, 2003; accepted February 7, 2003.
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References |
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1. de Gasparo M, Catt KJ, Inagami T, Wright JW, Unger T. International union of pharmacology. XXIII. The angiotensin II receptors. Pharmacol Rev. 2000; 52: 415–472.
2. Iwai N, Inagami T, Ohmichi N, Nakamura Y, Saeki Y, Kinoshita M. Differential regulation of rat AT1a and AT1b receptor mRNA. Biochem Biophys Res Commun. 1992; 188: 298–303.[CrossRef][Medline] [Order article via Infotrieve]
3. Sandberg K, Ji H, Clark AJ, Shapira H, Catt KJ. Cloning and expression of a novel angiotensin II receptor subtype. J Biol Chem. 1992; 267: 9455–9458.
4. Elton TS, Stephan CC, Taylor GR, Kimball MG, Martin MM, Durand JN, Oparil S. Isolation of two distinct type I angiotensin II receptor genes. Biochem Biophys Res Commun. 1992; 184: 1067–1073.[CrossRef][Medline] [Order article via Infotrieve]
5. Inagami T, Guo DF, Kitami Y. Molecular biology of angiotensin II receptors: an overview. J Hypertens Suppl. 1994; 12: S83–S94.[Medline] [Order article via Infotrieve]
6. Burson JM, Aguilera G, Gross KW, Sigmund CD. Differential expression of angiotensin receptor 1A and 1B in mouse. Am J Physiol. 1994; 267: E260–E267.[Medline] [Order article via Infotrieve]
7. Llorens-Cortes C, Greenberg B, Huang H, Corvol P. Tissular expression and regulation of type 1 angiotensin II receptor subtypes by quantitative reverse transcriptase-polymerase chain reaction analysis. Hypertension. 1994; 24: 538–548.
8. Gasc JM, Shanmugam S, Sibony M, Corvol P. Tissue-specific expression of type 1 angiotensin II receptor subtypes: an in situ hybridization study. Hypertension. 1994; 24: 531–537.
9. Jöhren O, Inagami T, Saavedra JM. AT1A, AT1B, and AT2 angiotensin II receptor subtype gene expression in rat brain. Neuroreport. 1995; 6: 2549–2552.[Medline] [Order article via Infotrieve]
10. Jöhren O, Saavedra JM. Expression of AT1A and AT1B angiotensin II receptor messenger RNA in forebrain of 2-wk-old rats. Am J Physiol. 1996; 271: E104–E112.[Medline] [Order article via Infotrieve]
11. Grady EF, Sechi LA, Griffin CA, Schambelan M, Kalinyak JE. Expression of AT2 receptors in the developing rat fetus. J Clin Invest. 1991; 88: 921–933.[Medline] [Order article via Infotrieve]
12. Jöhren O, Inagami T, Saavedra JM. Localization of AT2 angiotensin II receptor gene expression in rat brain by in situ hybridization histochemistry. Brain Res Mol Brain Res. 1996; 37: 192–200.[Medline] [Order article via Infotrieve]
13. Castren E, Saavedra JM. Repeated stress increases the density of angiotensin II binding sites in rat paraventricular nucleus and subfornical organ. Endocrinology. 1988; 122: 370–372.
14. Aguilera G, Kiss A, Luo X. Increased expression of type 1 angiotensin II receptors in the hypothalamic paraventricular nucleus following stress and glucocorticoid administration. J Neuroendocrinol. 1995; 7: 775–783.[Medline] [Order article via Infotrieve]
15. Leong DS, Terron JA, Falcon-Neri A, Armando I, Ito T, Jöhren O, Tonelli LH, Hoe KL, Saavedra JM. Restraint stress modulates brain, pituitary and adrenal expression of angiotensin II AT(1A), AT(1B) and AT(2) receptors. Neuroendocrinology. 2002; 75: 227–240.[CrossRef][Medline] [Order article via Infotrieve]
16. Rivier C, Vale W. Effect of angiotensin II on ACTH release in vivo: role of corticotropin-releasing factor. Regul Pept. 1983; 7: 253–258.[CrossRef][Medline] [Order article via Infotrieve]
17. Sumitomo T, Suda T, Nakano Y, Tozawa F, Yamada M, Demura H. Angiotensin II increases the corticotropin-releasing factor messenger ribonucleic acid level in the rat hypothalamus. Endocrinology. 1991; 128: 2248–2252.
18. Jezova D, Ochedalski T, Kiss A, Aguilera G. Brain angiotensin II modulates sympathoadrenal and hypothalamic pituitary adrenocortical activation during stress. J Neuroendocrinol. 1998; 10: 67–72.[CrossRef][Medline] [Order article via Infotrieve]
19. Iams SG, McMurthy JP, Wexler BC. Aldosterone, deoxycorticosterone, corticosterone, and prolactin changes during the lifespan of chronically and spontaneously hypertensive rats. Endocrinology. 1979; 104: 1357–1363.
20. McMurtry JP, Wexler BC. Hypersensitivity of spontaneously hypertensive rats (SHR) to heat, ether, and immobilization. Endocrinology. 1981; 108: 1730–1736.
21. Krauchi K, Wirz-Justice A, Willener R, Campbell IC, Feer H. Spontaneous hypertensive rats: behavioral and corticosterone response depend on circadian phase. Physiol Behav. 1983; 30: 35–40.[CrossRef][Medline] [Order article via Infotrieve]
22. Yamamoto J, Nakai M, Natsume T. Cardiovascular responses to acute stress in young-to-old spontaneously hypertensive rats. Hypertension. 1987; 9: 362–370.
23. McDougall SJ, Paull JR, Widdop RE, Lawrence AJ. Restraint stress: differential cardiovascular responses in Wistar- Kyoto and spontaneously hypertensive rats. Hypertension. 2000; 35: 126–129.
24. Berecek KH, Coshatt G, Narkates AJ, Oparil S, Wilson KM, Robertson J. Captopril and the response to stress in the spontaneously hypertensive rat. Hypertension. 1988; 11 (suppl I): I-144–I-147.[Medline] [Order article via Infotrieve]
25. Gaudet E, Blanc J, Elghozi JL. Role of angiotensin II and catecholamines in blood pressure variability responses to stress in SHR. Am J Physiol. 1996; 270: R1265–R1272.[Medline] [Order article via Infotrieve]
26. Saiki Y, Watanabe T, Tan N, Matsuzaki M, Nakamura S. Role of central ANG II receptors in stress-induced cardiovascular and hyperthermic responses in rats. Am J Physiol. 1997; 272: R26–R33.[Medline] [Order article via Infotrieve]
27. McDougall SJ, Roulston CA, Widdop RE, Lawrence AJ. Characterisation of vasopressin V(1A), angiotensin AT(1) and AT(2) receptor distribution and density in normotensive and hypertensive rat brain stem and kidney: effects of restraint stress. Brain Res. 2000; 883: 148–156.[CrossRef][Medline] [Order article via Infotrieve]
28. Schiffrin EL, Thome FS, Genest J. Vascular angiotensin II receptors in SHR. Hypertension. 1984; 6: 682–688.
29. Raizada MK, Muther TF, Sumners C. Increased angiotensin II receptors in neuronal cultures from hypertensive rat brain. Am J Physiol. 1984; 247: C364–C372.[Medline] [Order article via Infotrieve]
30. Hwang BH, Harding JW, Liu DK, Hibbard LS, Wieczorek CM, Wu JY. Quantitative autoradiography of 125I-[Sar1, Ile8]-angiotensin II binding in the brain of spontaneously hypertensive rats. Brain Res Bull. 1986; 16: 75–82.[CrossRef][Medline] [Order article via Infotrieve]
31. Song K, Kurobe Y, Kanehara H, Wada T, Inada Y, Nishikawa K, Miyazaki M. Mapping of angiotensin II receptor subtypes in peripheral tissues of spontaneously hypertensive rats by in vitro autoradiography. Clin Exp Pharmacol Physiol. 1995; 22 (suppl 1): S17–S19.[Medline] [Order article via Infotrieve]
32. Han NL, Sim MK. Hypothalamic angiotensin receptor subtypes in normotensive and hypertensive rats. Am J Physiol. 1998; 275: H703–H709.[Medline] [Order article via Infotrieve]
33. Iwai N, Yamano Y, Chaki S, Konishi F, Bardhan S, Tibbetts C, Sasaki K, Hasegawa M, Matsuda Y, Inagami T. Rat angiotensin II receptor: cDNA sequence and regulation of the gene expression. Biochem Biophys Res Commun. 1991; 177: 299–304.[CrossRef][Medline] [Order article via Infotrieve]
34. Raizada MK, Sumners C, Lu D. Angiotensin II type 1 receptor mRNA levels in the brains of normotensive and spontaneously hypertensive rats. J Neurochem. 1993; 60: 1949–1952.[Medline] [Order article via Infotrieve]
35. Roesch DM, Tian Y, Verbalis JG, Sandberg K. Rat model for investigating ACTH-independent angiotensin-induced aldosterone secretion. J Renin Angiotensin Aldosterone Syst. 2000; 1: 36–39.
36. Palkovits M, Brownstein MJ. Maps and Guide to Microdissection of the Rat Brain. New York, NY: Elsevier; 1988.
37. Murphy TJ, Alexander RW, Griendling KK, Runge MS, Bernstein KE. Isolation of a cDNA encoding the vascular type-1 angiotensin II receptor. Nature. 1991; 351: 233–236.[CrossRef][Medline] [Order article via Infotrieve]
38. Ruan X, Wagner C, Chatziantoniou C, Kurtz A, Arendshorst WJ. Regulation of angiotensin II receptor AT1 subtypes in renal afferent arterioles during chronic changes in sodium diet. J Clin Invest. 1997; 99: 1072–1081.[Medline] [Order article via Infotrieve]
39. Kambayashi Y, Bardhan S, Takahashi K, Tsuzuki S, Inui H, Hamakubo T, Inagami T. Molecular cloning of a novel angiotensin II receptor isoform involved in phosphotyrosine phosphatase inhibition. J Biol Chem. 1993; 268: 24543–24546.
40. Nudel U, Zakut R, Shani M, Neuman S, Levy Z, Yaffe D. The nucleotide sequence of the rat cytoplasmic beta-actin gene. Nucleic Acids Res. 1983; 11: 1759–1771.
41. Jöhren O, Neidert SJ, Kummer M, Dendorfer A, Dominiak P. Prepro-orexin and orexin receptor mRNAs are differentially expressed in peripheral tissues of male and female rats. Endocrinology. 2001; 142: 3324–3331.
42. Jöhren O, Sanvitto GL, Egidy G, Saavedra JM. Angiotensin II AT1A receptor mRNA expression is induced by estrogen- progesterone in dopaminergic neurons of the female rat arcuate nucleus. J Neurosci. 1997; 17: 8283–8292.
43. Timmermans PB, Wong PC, Chiu AT, Herblin WF, Benfield P, Carini DJ, Lee RJ, Wexler RR, Saye JA, Smith RD. Angiotensin II receptors and angiotensin II receptor antagonists. Pharmacol Rev. 1993; 45: 205–251.[Medline] [Order article via Infotrieve]
44. Brasch H, Sieroslawski L, Dominiak P. Angiotensin II increases norepinephrine release from atria by acting on angiotensin subtype 1 receptors. Hypertension. 1993; 22: 699–704.
45. Morris M, Li P, Callahan MF, Oliverio MI, Coffman TM, Bosch SM, Diz DI. Neuroendocrine effects of dehydration in mice lacking the angiotensin AT1a receptor. Hypertension. 1999; 33: 482–486.
46. Davisson RL, Oliverio MI, Coffman TM, Sigmund CD. Divergent functions of angiotensin II receptor isoforms in the brain. J Clin Invest. 2000; 106: 103–106.[Medline] [Order article via Infotrieve]
47. Gutkind JS, Castren E, Saavedra JM. Decreased angiotensin II binding affinity and binding capacity in the anterior pituitary gland of adult spontaneously hypertensive rats. Life Sci. 1988; 43: 445–451.[CrossRef][Medline] [Order article via Infotrieve]
48. Lenkei Z, Nuyt AM, Grouselle D, Corvol P, Llorens-Cortes C. Identification of endocrine cell populations expressing the AT1B subtype of angiotensin II receptors in the anterior pituitary. Endocrinology. 1999; 140: 472–477.
49. Steele MK, Negro-Vilar A, McCann SM. Effect of angiotensin II on in vivo and in vitro release of anterior pituitary hormones in the female rat. Endocrinology. 1981; 109: 893–899.
50. Aguilera G, Hyde CL, Catt KJ. Angiotensin II receptors and prolactin release in pituitary lactotrophs. Endocrinology. 1982; 111: 1045–1050.
51. Sobel D, Vagnucci A. Angiotensin II mediated ACTH release in rat pituitary cell culture. Life Sci. 1982; 30: 1281–1286.[CrossRef][Medline] [Order article via Infotrieve]
52. Robberecht W, Denef C. Enhanced ANG II activity in anterior pituitary cell aggregates from hypertensive rats. Am J Physiol. 1988; 255: R407–R411.[Medline] [Order article via Infotrieve]
53. Oliverio MI, Best CF, Smithies O, Coffman TM. Regulation of sodium balance and blood pressure by the AT(1A) receptor for angiotensin II. Hypertension. 2000; 35: 550–554.
54. Light KC, Girdler SS, Sherwood A, Bragdon EE, Brownley KA, West SG, Hinderliter AL. High stress responsivity predicts later blood pressure only in combination with positive family history and high life stress. Hypertension. 1999; 33: 1458–1464.
55. Furuta H, Guo DF, Inagami T. Molecular cloning and sequencing of the gene encoding human angiotensin II type 1 receptor. Biochem Biophys Res Commun. 1992; 183: 8–13.[CrossRef][Medline] [Order article via Infotrieve]
56. Curnow KM, Pascoe L, Davies E, White PC, Corvol P, Clauser E. Alternatively spliced human type 1 angiotensin II receptor mRNAs are translated at different efficiencies and encode two receptor isoforms. Mol Endocrinol. 1995; 9: 1250–1262.
57. Martin MM, Willardson BM, Burton GF, White CR, McLaughlin JN, Bray SM, Ogilvie JW Jr, Elton TS. Human angiotensin II type 1 receptor isoforms encoded by messenger RNA splice variants are functionally distinct. Mol Endocrinol. 2001; 15: 281–293.
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