*106165	GeneTests, Links
ANGIOTENSIN RECEPTOR 1; AGTR1

Alternative titles; symbols

ANGIOTENSIN II RECEPTOR, VASCULAR TYPE 1; AT2R1
ANGIOTENSIN RECEPTOR 1A; AGTR1A
AT1R
ANGIOTENSIN RECEPTOR 1B, INCLUDED; AGTR1B, INCLUDED

Gene map locus 3q21-q25

TEXT

DESCRIPTION

Angiotensin II (see 106150) is an important effector controlling blood pressure and volume in the cardiovascular system. Its importance is reflected by the efficacy of angiotensin-converting enzyme inhibitors in the treatment of hypertension and congestive heart failure. Angiotensin II interacts with 2 pharmacologically distinct subtypes of cell surface receptors, types 1 and 2 (AGTR2; 300034). Type 1 receptors seem to mediate the major cardiovascular effects of angiotensin II (Murphy et al., 1991).

CLONING

By expression cloning, Murphy et al. (1991) isolated a cDNA encoding the type 1 receptor. Hydropathic modeling of the deduced protein suggested that it shares the 7-transmembrane-region motif with the G protein-coupled receptor superfamily. Sasaki et al. (1991) isolated the corresponding bovine gene. Takayanagi et al. (1992) cloned and sequenced a cDNA encoding this receptor in the human, and by Northern blot analysis they demonstrated its expression in human liver, lung, adrenal, and adrenocortical adenomas, but not in pheochromocytomas. Bergsma et al. (1992) and Mauzy et al. (1992) also cloned and characterized a human AGTR1 cDNA.

In the rat, Elton et al. (1992) identified 2 distinct type I angiotensin II receptor genes. The first of these corresponds to the published rat vascular cDNA sequence; the second corresponds to a novel receptor. By Southern blot analysis of somatic cell hybrids, Szpirer et al. (1993) showed that in the rat there are 2 nonsyntenic genes, one on chromosome 17 and the other on chromosome 2.

Mauzy et al. (1992) and Konishi et al. (1994) found evidence for a second angiotensin receptor gene in the human genome. The 2 subtypes of angiotensin II type 1 receptors, 1A and 1B (AGTR1B), have been identified in human, rat, and mouse. These receptors are splice variants (Scott, 2001). AGTR1A and AGTR1B share substantial sequence homology and wide tissue distributions (Ito et al., 1995). The angiotensin II 1A receptor seems to predominate in many tissues, but not in adrenal or anterior pituitary glands, and expression of the 2 types of receptors may be differentially regulated in the heart and the adrenals. This differential tissue distribution and regulation of angiotensin II receptor subtypes may serve to modulate the biologic effects of angiotensin II.

Martin et al. (2001) stated that human tissues expressing AGTR1 can synthesize 4 distinct alternatively spliced AGTR1 mRNA transcripts, designated AGTR1A through AGTR1D. They showed that the relative abundance of these mRNA transcripts varies widely in human tissues, suggesting that each splice variant is functionally distinct.

GENE FUNCTION

Herzig et al. (1997) studied AGTR1 promoter activity during cardiac hypertrophy. A luciferase reporter construct containing the AGTR1 promoter was injected into rat hearts in vivo. Pressure overload cardiac hypertrophy was induced by surgical constriction of the suprarenal aorta. In hypertrophied myocardium, luciferase activity increased by 160% compared to normal myocardium; this effect was blocked by introducing mutations into either the AP-1 or GATA consensus binding sites within the AGTR1 promoter, but these mutations did not affect basal luciferase activity. Pressure overload increased the level of DNA binding at the AP-1 site, concomitant with significant increases in c-fos and jun-B expression assessed by gel mobility shift assays. The level of GATA4 DNA binding to the AP-1 and GATA consensus sites was also greatly increased in overloaded hearts. These results demonstrated that the AGTR1 regulatory region is active in cardiac muscle and suggested that part of the pressure overload response is mediated by interaction at the AP-1 and GATA consensus sites.

Pharmacologic agents that either block the formation of angiotensin II or interrupt its action by antagonizing the AGT1-receptor are highly successful in the treatment of angiotensin II-dependent hypertension. Most notable among these agents is losartan, an AGT1-receptor antagonist that has been found to be an effective anti-hypertension drug without the usual side effects. This, coupled with the demonstration that polymorphism in the AGTR1 gene is associated with hypertension (Bonnardeaux et al., 1994), further supports the notion that the AGT1 receptor is an important target for the control of angiotensin II-dependent hypertension. In spite of the availability of excellent drugs for the control of hypertension, Iyer et al. (1996) explored the possibility that gene therapy could be used. They demonstrated that the delivery of angiotensin type 1 receptor antisense by a retrovirally-mediated delivery system resulted in a selective attenuation of the cellular actions of angiotensin II in the neurons of the spontaneously hypertensive (SH) rat model. A single injection normalized blood pressure in the SH rat on a long-term basis. The use of this approach in patients was proposed.

Martens et al. (1998) showed that normalization of blood pressure by angiotensin II type 1 receptor antisense (AGTR1-AS) gene therapy prevented the development of renal vascular and cardiac pathophysiologic changes. Intracardiac delivery of AGTR1-AS in neonates prevented the development of hypertension in SH rats for at least 120 days.

Haywood et al. (1997) studied a series of myocardial biopsies from 9 normal donor hearts and 12 failing hearts with dilated or ischemic cardiomyopathy. Using a competitive RT-PCR technique, they showed that AGTR1A mRNA levels in failing hearts were 2.5 times lower than in normal hearts. Haywood et al. (1997) suggested that this finding may influence the use of specific AGTR1 antagonists in patients with heart failure.

Wallukat et al. (1999) reported that patients with preeclampsia (189800) develop autoantibodies against the angiotensin AT1 receptor. They investigated 25 patients with preeclampsia and compared them with 12 normotensive pregnant women and 10 pregnant women with essential hypertension. Immunoglobulin from all preeclamptic patients stimulated the AT1 receptor, as detected by the chronotropic responses in cultured neonatal rat cardiomyocytes; immunoglobulin from controls had no effect. The increased autoimmune activity decreased after delivery. The results suggested that preeclamptic patients develop stimulatory autoantibodies against the second extracellular AT1 receptor loop. The effect appeared to be mediated by protein kinase C (see 176960) because the PKC inhibitor calphostin C prevented the stimulatory effect. These antibodies may participate in the angiotensin II-induced vascular lesions seen in patients with preeclampsia.

Martin et al. (2001) showed that the AGTR1B mRNA splice variant encodes a novel long AGTR1 isoform in vivo that has significantly diminished affinity for angiotensin II when compared with the short AGTR1 isoform encoded by the AGTR1A splice variant. This reduced agonist affinity caused a significant shift to the right in the dose-response curve for angiotensin II-induced inositol trisphosphate production and Ca(2+) mobilization of the long AGTR1 when compared with that of the short AGTR1. The authors concluded that the functional differences between these isoforms allows angiotensin II responsiveness to be fine tuned by regulating the relative abundance of the long and short AGTR1 isoform expressed in a given human tissue.

The vasopressor angiotensin II regulates vascular contractility and blood pressure through binding to type 1 angiotensin II receptors. Bradykinin, a vasodepressor, is a functional antagonist of angiotensin II. The 2 hormone systems are interconnected by the angiotensin-converting enzyme, which releases angiotensin II from its precursor and inactivates the vasodepressor bradykinin. AbdAlla et al. (2000) demonstrated that the type 1 angiotensin II receptor and the bradykinin B2 receptor (113503) also communicate directly with each other. They form stable heterodimers, causing increased activation of G-alpha-q (600998) and G-alpha-i proteins, the 2 major signaling proteins triggered by the type 1 angiotensin II receptor. Furthermore, the endocytotic pathway of both receptors changes with heterodimerization.

AbdAlla et al. (2004) reported that intracellular factor XIIIA transglutaminase (134570) crosslinks agonist-induced AT1 receptor homodimers via gln315 in the C-terminal tail of the AT1 receptor. The crosslinked dimers displayed enhanced signaling and desensitization in vitro and in vivo. Inhibition of angiotensin II release or of factor XIIIA activity prevented formation of crosslinked AT1 receptor dimers. In agreement with this finding, factor XIIIA-deficient individuals lacked crosslinked AT1 dimers. Elevated levels of crosslinked AT1 dimers were present on monocytes of patients with hypertension and correlated with an enhanced angiotensin II-dependent monocyte adhesion to endothelial cells. Elevated levels of crosslinked AT1 receptor dimers on monocytes could sustain the process of atherogenesis, because inhibition of angiotensin II generation or of intracellular factor XIIIA activity suppressed the appearance of crosslinked AT1 receptors and symptoms of atherosclerosis in ApoE (107741)-deficient mice.

Kuba et al. (2005) hypothesized that the severe acute respiratory syndrome (SARS) coronavirus Spike (S) protein could adversely affect acute lung injury through modulation of its cellular receptor, ACE2 (300335). Pull-down and FACS analyses demonstrated that S protein bound to ACE2 and downregulated ACE2 surface expression. Treatment of wildtype mice with S protein or with its truncated ACE2-binding domain worsened lung function. Acid challenge of these mice further augmented pathology to lung parenchyma. The S protein localized to bronchial epithelial cells, inflammatory exudates, and alveolar pneumocytes. Furthermore, S protein downregulated Ace2 expression in acid-treated wildtype mice and increased lung levels of the angiotensin II. Blockage of Agtr1, which mediates angiotensin II-induced vascular permeability and severe acute lung injury, attenuated lung injury in S protein-treated mice. Kuba et al. (2005) concluded that SARS coronavirus S protein can exaggerate acute lung failure through deregulation of the renin-angiotensin system, and that lung failure can be rescued by inhibition of AGTR1.

Using luciferase reporter analysis, Martin et al. (2006) showed that MIRN155 (609337) directly interacted with the 3-prime UTR of AT1R mRNA. Transfection of MIRN155 into human primary lung fibroblasts reduced endogenous expression of AT1R and AT1R-induced activation of ERK1 (MAPK3; 601795)/ERK2 (MAPK1; 176948). Treatment of primary lung fibroblasts with TGFB1 (190180) decreased MIRN155 expression and increased AT1R expression. Martin et al. (2006) concluded that MIRN155 translationally represses expression of the AT1R protein and that MIRN155-mediated translational repression can be regulated by physiologic stimuli.

GENE STRUCTURE

Furuta et al. (1992) studied the AGTR1 genomic sequence and demonstrated that the coding region is contained in a single exon. By comparing genomic DNA and cDNA sequences, Guo et al. (1994) demonstrated that the AGTR1 gene consists of at least 5 exons and spans more than 55 kb of genomic DNA. The size of the exons ranges from 59 to 2,014 bp. Four of the exons encode 5-prime untranslated sequences. Multiple transcription initiation sites were observed by primer extension experiments.

MAPPING

Curnow et al. (1992) mapped the AGTR1 gene to 3q by PCR analysis of DNA from a panel of human-hamster somatic cell hybrids. In an analysis of cDNA and genomic clones, variation was found, making these clones potentially useful in testing the hypothesis that genetic variations in AGTR1 function are associated with a tendency to develop hypertension. Using a somatic cell hybrid regional mapping panel, the AGTR1 gene was further regionalized to 3q21-q25 (Gemmill and Drabkin, 1991). By Southern blot analysis of somatic cell hybrids, Szpirer et al. (1993) likewise mapped the human AGTR1 gene to chromosome 3.

MOLECULAR GENETICS

Gribouval et al. (2005) studied 11 individuals with renal tubular dysgenesis (267430) belonging to 9 families and found that they had homozygous or compound heterozygous mutations in the genes encoding renin (REN; 179820), angiotensinogen (AGT; 106150), angiotensin-converting enzyme (ACE; 106180), or angiotensin II receptor type 1 (AGTR1). They proposed that renal lesions and early anuria result from chronic low perfusion pressure of the fetal kidney, a consequence of renin-angiotensin system inactivity. This appeared to be the first identification of a renal mendelian disorder linked to genetic defects in the renin-angiotensin system, highlighting the crucial role of the renin-angiotensin system in human kidney development.

ANIMAL MODEL

Ito et al. (1995) examined the physiologic and genetic functions of the type 1A receptor for angiotensin II by disrupting the mouse gene encoding this receptor in embryonic stem cells by gene targeting. Agtr1a-null mice were born in expected numbers and the histomorphology of their kidneys, heart, and vasculature was normal. Type 1 receptor-specific angiotensin II binding was not detected in the kidneys of homozygous mutant animals, and heterozygotes exhibited a reduction in renal type 1 receptor-specific binding to approximately 50% of wildtype levels. Pressor responses to infused angiotensin II were virtually absent in homozygous mice and were altered in heterozygotes. Compared with wildtype controls, systolic blood pressure was reduced by 12 mmHg in heterozygous mice and by 24 mmHg in homozygous mutant mice.

Sasaki et al. (2002) found that Agtr1a knockout mice have decreased angiogenesis and fewer well-developed collateral vessels in response to hindlimb ischemia as compared to wildtype mice. Similar results were found in wildtype mice treated with the AGTR1a blocker TCV-116. Agtr1a -/- mice had decreased infiltration of inflammatory mononuclear cells (MNCs) in their ischemic tissue and decreased expression of monocyte chemoattractant protein-1 (158150) and vascular endothelial growth factor (VEGF; 192240). VEGF was found to be expressed by the infiltrated macrophages and T lymphocytes. The impaired angiogenesis in Agtr1a -/- mice was rescued by intramuscular transplantation of MNCs obtained from wildtype mice.

Rodents are unique in carrying duplicated angiotensin type 1 receptor genes, Agtr1a and Agtr1b. After separately generating Agtr1a and Agtr1b null mutant mice by gene targeting, Tsuchida et al. (1998) generated double mutant mice homozygous for null mutations at both loci by mating the single gene mutants. The homozygous, doubly mutant mice were characterized by normal in utero survival but decreased ex utero survival rate. After birth they showed low body weight gain, marked hypotension, and abnormal kidney morphology including delayed maturation in glomerular growth, hypoplastic papillae, and renal arterial hypertrophy. These abnormal features were quantitatively similar to those found in mutant mice homozygous for the null angiotensinogen mutation, indicating that major biologic functions of endogenous angiotensinogen elucidated by the abnormal phenotypes of the null mutant are mediated by the AGT1 receptors. Two of 28 double nullizygotes inspected had a ventricular septal defect. This finding was considered to be in concert with the findings in human that an abnormality in 3q on which the type 1 angiotensin receptor is located, accompanies ventricular septal defect (Wilson et al., 1985), although Tsuchida et al. (1998) considered that these findings may be coincidental.

The classically recognized functions of the renin-angiotensin system are mediated by type 1 (AT1) angiotensin receptors. As indicated earlier, whereas man possesses a single AT1 receptor, there are 2 AT1 receptor isoforms in rodents, AT1A and AT1B, that are products of separate genes, Agtr1a and Agtr1b. Oliverio et al. (1998) generated mice lacking AT1B (Agtr1b -/-) and other mice lacking both AT1A and AT1B receptors. Agtr1b -/- mice were healthy, without an abnormal phenotype. In contrast, mice who were homozygous for disruptions of both Agtr1a and Agtr1b had diminished growth, vascular thickening within the kidney, and atrophy of the inner renal medulla. This phenotype was virtually identical to that seen in angiotensinogen-deficient mice (see 106150) and in mice deficient in angiotensin-converting enzyme (106180). The double knockout mice had no systemic pressor response to infusions of angiotensin II, but they responded normally to another vasoconstrictor, epinephrine. Blood pressure was reduced substantially in the double knockout mice, and following administration of an angiotensin-converting enzyme inhibitor, their blood pressure increased paradoxically. Oliverio et al. (1998) suggested that this was a result of interruption of AT2-receptor signaling. In summary, their studies suggested that both AT1 receptors promote somatic growth and maintenance of normal kidney structure. The absence of either of the AT1 receptor isoforms alone can be compensated in varying degrees by the other isoform.

Harada et al. (1998) suggested a role for AGTR1 in the generation of reperfusion arrhythmias following restoration of blood flow to ischemic or infarcted myocardium. The authors produced transient coronary artery occlusion in AGTR1 knockout mice and wildtype controls. Mice lacking AGTR1 developed significantly fewer episodes of ventricular arrhythmia after restoration of coronary blood flow. Administration of a selective AGTR1 antagonist before induction of myocardial ischemia significantly blocked the development of reperfusion arrhythmias in wildtype mice, a phenomenon that may have implications in human cardiologic practice.

To determine whether angiotensin II can induce cardiac hypertrophy directly via myocardial angiotensin receptor changes in the absence of vascular changes, Paradis et al. (2000) generated transgenic mice overexpressing the human AGTR1 gene under the control of the mouse alpha-myosin heavy chain promoter. Cardiomyocyte-specific overexpression of AGTR1 induced, in basal conditions, morphologic changes of myocytes and nonmyocytes that mimicked those observed during the development of cardiac hypertrophy in humans and in other mammals. These mice displayed significant cardiac hypertrophy and remodeling with increased expression in the ventricle of atrial natriuretic factor (ANF; 108780) and interstitial collagen deposition, and they died prematurely of heart failure. Neither systolic blood pressure nor heart rate were changed.

Using a kidney cross-transplantation strategy to separate the action of AGTR1 receptor pools in the kidney from those in systemic tissues, Crowley et al. (2006) demonstrated that mice transplanted with Agtr1a -/- kidneys did not develop hypertension or cardiac hypertrophy after infusion of angiotensin II, whereas Agtr1a-null mice that had Agtr1a +/+ kidneys recapitulated the hypertension and cardiac hypertrophy phenotype of wildtype mice. Crowley et al. (2006) concluded that renal AGTR1 receptors are absolutely required for the development of angiotensin II-dependent hypertension and cardiac hypertrophy and that the major mechanism of action of renin-angiotensin system inhibitors in hypertension is attenuation of angiotensin II effects in the kidney.

HISTORY

Mukoyama et al. (1993), Kambayashi et al. (1993), and Razdan and Kroll (1996) reported the cloning of a novel angiotensin receptor II cDNA, which was symbolized AGTRL2 by the HUGO Nomenclature Committee, but the sequence was later found to be an orphan transcript.

ALLELIC VARIANTS
(selected examples)

.0001 HYPERTENSION, ESSENTIAL, SUSCEPTIBILITY TO [AGTR1, 1166A-C POLYMORPHISM ]

Variants in the human AGTR1A gene may affect blood pressure in the human. Bonnardeaux et al. (1994) identified an association between several AGTR1A gene polymorphisms and hypertension. Specifically, an A-to-C variant, located in the 3-prime untranslated region at nucleotide 1166, showed a significantly elevated frequency in 206 Caucasian patients with essential hypertension. Wang et al. (1997) did a case-control study of the 1166A-C variant in 108 Caucasian hypertensive patients with a strong family history (2 affected parents) and early onset disease. The frequency of the 1166C allele was 0.40 in hypertensives and 0.29 in normotensives.

Kobashi et al. (2004) genotyped 114 Japanese patients with severe hypertension in pregnancy (HP) and 291 normal pregnancy controls. Among primiparous patients, the frequency of the AC and CC genotypes at nucleotide 1166 of the AGTR1 gene was significantly higher in severe HP than in the controls. A multivariate analysis with the AC and CC genotypes at nucleotide 1166 of the AGTR1 gene and TT genotype at codon 235 of the AGT gene (106150.0001) revealed that these were independently associated with primiparous severe HP.

.0002 STATURE AS A QUANTITATIVE TRAIT [AGTR1, 573C-T ]

Chaves et al. (2004) analyzed the influence on height (see 606255) of the polymorphisms G-6A of the angiotensinogen gene (106150.0002), insertion/deletion (I/D) of the angiotensin-converting enzyme (106180.0001), and C573T of the AGTR1 gene on a healthy, middle-age population. A total of 370 (194 women) healthy normotensive Caucasian subjects aged 25 to 50 years old were selected from the general population. A significant association was found between height and the C573T polymorphism in women (P less than 0.001). After adjustment for age, this association remained significant (P less than 0.002). Likewise, the I/D polymorphism was associated with height (P = 0.002) in women. It remained significant after adjustment for age and the lowest height for the DD genotype (II, 1.629 +/- 0.011 m; ID, 1.603 +/- 0.006 m; DD, 1.591 +/- 0.007 m; P = 0.016). For both C573T and I/D polymorphisms, there was an allele dosage effect. Moreover, an additive and independent effect of the C573T polymorphism (P = 0.006) and the I/D polymorphism (P = 0.045) on height was observed. In contrast, no association with height was observed for the G-6A polymorphism.

.0003 RENAL TUBULAR DYSGENESIS [AGTR1, 1-BP INS, 110T]

In 2 sibs with renal tubular dysgenesis (267430) from a nonconsanguineous family, Gribouval et al. (2005) found compound heterozygosity for 2 mutations in the AGTR1 gene. The mutation inherited from the heterozygous mother, who was of Slovenian derivation, was a 1-bp insertion, 110_111insT, resulting in a frameshift and a premature stop codon (I37fs74X). The mutation inherited from the heterozygous father, who was of Italian ancestry, was a missense mutation (106165.0004).

.0004 RENAL TUBULAR DYSGENESIS [AGTR1, THR282MET ]

The mutation carried by the paternal allele in the 2 cases described by Gribouval et al. (2005) was an 845C-T transition in exon 4 of the AGTR1 gene that resulted in substitution of methionine for threonine-282 (T282M). See 106165.0003.

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CONTRIBUTORS

Paul J. Converse - updated : 5/16/2007
Marla J. F. O'Neill - updated : 2/5/2007
Victor A. McKusick - updated : 9/27/2005
Paul J. Converse - updated : 9/13/2005
John A. Phillips, III - updated : 8/2/2005
Stylianos E. Antonarakis - updated : 1/19/2005
Victor A. McKusick - updated : 5/13/2004
Deborah L. Stone - updated : 9/12/2002
John A. Phillips, III - updated : 7/26/2001
Ada Hamosh - updated : 9/6/2000
Victor A. McKusick - updated : 2/9/2000
Victor A. McKusick - updated : 4/20/1999
Victor A. McKusick - updated : 3/1/1999
Paul Brennan - updated : 6/1/1998
Paul Brennan - updated : 5/16/1998
Victor A. McKusick - updated : 3/20/1998
Paul Brennan - updated : 11/10/1997
Victor A. McKusick : 4/24/1997

CREATION DATE

Victor A. McKusick : 6/24/1991

EDIT HISTORY

mgross : 5/16/2007
mgross : 5/16/2007
wwang : 2/5/2007
carol : 5/23/2006
joanna : 10/4/2005
alopez : 9/28/2005
terry : 9/27/2005
mgross : 9/13/2005
alopez : 8/4/2005
alopez : 8/2/2005
mgross : 1/19/2005
mgross : 1/19/2005
alopez : 1/6/2005
tkritzer : 5/25/2004
terry : 5/13/2004
carol : 3/8/2004
carol : 3/8/2004
carol : 9/12/2002
cwells : 8/2/2001
cwells : 7/26/2001
alopez : 7/9/2001
carol : 3/20/2001
carol : 3/20/2001
alopez : 9/7/2000
alopez : 9/6/2000
alopez : 9/6/2000
mgross : 3/2/2000
terry : 2/9/2000
carol : 4/21/1999
terry : 4/20/1999
carol : 3/22/1999
terry : 3/1/1999
terry : 3/1/1999
carol : 10/6/1998
carol : 6/2/1998
terry : 6/1/1998
carol : 5/16/1998
carol : 4/7/1998
terry : 3/28/1998
alopez : 3/25/1998
terry : 3/20/1998
alopez : 1/16/1998
alopez : 12/18/1997
terry : 4/24/1997
terry : 4/24/1997
terry : 4/21/1997
mark : 11/18/1996
terry : 10/23/1996
mark : 5/8/1995
jason : 7/1/1994
carol : 11/3/1993
carol : 3/25/1993
carol : 1/6/1993
carol : 11/5/1992

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