Disease relevance of Agtr1a

• When compared with Agtr1a null mutant chimeras, the control chimeras had more extensive cardiac fibrosis, most prominently in perivascular regions [1].
• Within a given Agtr1a -/- <--> +/+ mouse, however, the degree of JG hypertrophy/hyperplasia and the expression of renin mRNA and protein were identical between Agtr1a +/+ and Agtr1a -/- cells [2].
• This study demonstrates that Agtr1a-/- mice exhibit attenuation of diet-induced weight gain and adiposity through increased energy expenditure [3].
• The Agtr1a-/- mice exhibited the attenuation of diet-induced body weight gain and adiposity, and insulin resistance relative to wild-type littermates (Agtr1a+/+ mice) [3].
• The low blood pressures of Agtr1a-/- mice decreased further while on a low-salt diet from 82+/-3 to 69+/-3 mm Hg (P<0.03) [4].

Psychiatry related information on Agtr1a

• We measured light/dark rhythms in BP, heart rate (HR) and drinking behavior in Ang AT1a deficient (AT1a -/-) and wild type (AT1a +/+) mice with arterial telemetric catheters [5].

High impact information on Agtr1a

• Elevated levels of crosslinked AT1 dimers were present on monocytes of patients with the common atherogenic risk factor hypertension and correlated with an enhanced angiotensin II-dependent monocyte adhesion to endothelial cells [6].
• In agreement with this finding, factor XIIIA-deficient individuals lacked crosslinked AT1 dimers [6].
• The type-1 receptor (AT1) mediates the vasopressive and aldosterone-secreting effects of angiotensin II, but the function of the type-2 receptor (AT2) is unknown, although it is expressed in both adult and embryonic life [7].
• Moreover, the number of infiltrated macrophages was significantly lower in AT1a-/- mice than in WT mice, and double-immunofluorescence staining revealed that these macrophages expressed VEGF protein intensively [8].
• These effects were not due to reduced systemic blood pressure (SBP), because hydralazine treatment preserved angiogenesis in WT mice although it reduced SBP to a level similar to that of AT1a(-/-) mice [9].

Chemical compound and disease context of Agtr1a

• Furthermore, stimulation of AT1A by exogenous Ang II at a subpressor dose significantly exacerbated cardiac hypertrophy and dramatically augmented interstitial fibrosis in GC-A-KO mice but not in wild-type animals [10].
• Moreover, it has been reported that pressure overload-induced cardiac hypertrophy is completely prevented by ACE inhibitors in vivo and that the stored angiotensin II (Ang II) is released from cardiac myocytes in response to mechanical stretch and induces cardiomyocyte hypertrophy through the Ang II type 1 receptor (AT1) in vitro [11].
• On this basis we hypothesized that BLEO-induced apoptosis and lung fibrosis in mice would be inhibited by the AT1 antagonist losartan (LOS) or by targeted deletion of the AT1 gene [12].
• We have thus investigated whether the angiotensin II type 1 (AT1) receptor antagonist, telmisartan, can inhibit the accelerated renal fibrosis and excess oxidative stress, which occurs after unilateral ureteral obstruction (UUO) in acatalasemic mice [13].
• Angiotensin II receptors of the AT1 subtype were very highly expressed in medroxyprogesterone-induced ductal adenocarcinomas of the mammary gland in BALB/c mice [14].

Biological context of Agtr1a

• In Agtr1a -/- <--> +/+ mice, these changes were proportional to the degree of chimerism [2].
• To characterize the mode of action of angiotensin II (Ang II) in cardiac remodeling, we generated chimeric mice that are made of both homozygous Ang II receptor type 1A gene (Agtr1a) null mutant cells and Agtr1a intact cells expressing the lacZ gene (ROSA26) [1].
• Blood pressure is reduced substantially in the Agtr1a -/- Agtr1b -/- mice and following administration of an angiotensin converting enzyme inhibitor, their blood pressure increases paradoxically [15].
• The heterozygous Agtr1a-deficient mice (Agtr1a+/- mice) also exhibited metabolic phenotypes similar to those of Agtr1a-/- mice [3].
• ECF volume depletion by dietary sodium restriction enhanced Agtr1a gene expression in the adrenal gland of wild-type mice [16].

Anatomical context of Agtr1a

• The proliferating cardiac fibroblasts identified by bromodeoxyuridine staining were present predominantly in the areas surrounded by Agtr1a intact cardiomyocytes [1].
• Both Agtr1a null and intact myocytes and interstitial cells independently form areas that are randomly distributed throughout the heart [1].
• Using Agtr1a(-/-) mice, which lack AT(1A) receptors for angiotensin II, we have identified a novel function of the RAS to modulate the immune system [17].
• Using mouse embryonic fibroblasts derived from Agtr1a+/+ and Agtr1a-/- mice, we found no significant difference between genotypes in the ability to differentiate into lipid-laden mature adipocytes [3].
• To understand the functional role of Agtr1 in adipose tissue growth and metabolism in vivo, we examined the metabolic phenotypes of mice lacking Agtr1a (Agtr1a-/- mice) during a high-fat diet [3].

Associations of Agtr1a with chemical compounds

• When control chimeric mice made of wild-type cells and ROSA26 cells (i.e., both carrying intact Agtr1a) were infused with Ang II, fibroblast proliferation was found equally in these cardiomyocyte types [1].
• Agtr1a -/-Agtr1b -/- mice have no systemic pressor response to infusions of angiotensin II, but they respond normally to another vasoconstrictor, epinephrine [15].
• In the basal state, plasma vasopressin levels are similar in wild-type controls and Agtr1a -/- mice [18].
• Although urinary sodium excretion was substantially reduced in both groups during the low-salt diet, cumulative sodium balances became negative in Agtr1a-/- mice despite a 6-fold increase in urinary aldosterone [4].
• The residual constrictor effect observed during AT1 receptor blockade and sensitive to PD 123319 appears to be mediated by a non-AT1 receptor [19].

Physical interactions of Agtr1a

• We investigated whether GC-A interacts with AT1A signaling in the heart by target deletion and pharmacological blockade or stimulation of AT1A in mice [10].

Regulatory relationships of Agtr1a

• The carboxyl-terminal cytoplasmic domain of the angiotensin II type 1 (AT1) receptor has recently been shown to interact with several classes of cytoplasmic proteins that regulate different aspects of AT1 receptor physiology [20].
• METHODS AND RESULTS: We generated double-knockout (KO) mice for GC-A and AT1A by crossing GC-A-KO mice and AT1A-KO mice and blocked AT1 with a selective antagonist, CS-866 [10].
• Collectively, these findings suggest that Ang II impairs functional hyperemia by activating AT1 receptors and inducing ROS production via a gp91phox containing NADPH oxidase [21].
• RESULTS: The normal postnatal up-regulation of kininase II was organ-specifically suppressed in Agtr1-/- kidneys at 2 and 3 weeks of age [22].
• AT1A receptor deficiency-induced reductions in atherosclerosis were independent of systolic blood pressure and measurements of oxidation and chemoattractants [23].

Other interactions of Agtr1a

• Agtr1a-/-, Agtr1b-/- mice are characterized by normal in utero survival but decreased ex utero survival rate [24].
• These abnormal phenotypes are quantitatively similar to those found in mutant mice homozygous for the angiotensinogen gene (Agt-/-), indicating that major biological functions of endogenous Ang elucidated by the abnormal phenotypes of Agt-/- are mediated by the AT1 receptors [24].
• We examined the possibility of whether angiotensin (Ang) II type 1 (AT1) and type 2 (AT2) receptor stimulation differentially regulates collagen production in mouse skin fibroblasts [25].
• In contrast to wild-type and AT1-/- mice, this treatment led to severe atherosclerotic lesion formation in the aortic sinus and the aorta (oil red O staining) and to an impaired endothelium-dependent vasodilation (organ chamber experiments with isolated aortic segments) in ApoE-/- mice [26].
• Ang II decreased basal and IGF-I-induced collagen production and inhibited TIMP-1 expression in neonatal skin fibroblasts prepared from AT1a knockout (KO) mice [25].

Analytical, diagnostic and therapeutic context of Agtr1a

• The ATRAP-AT1a receptor association was confirmed by affinity chromatography, by specific co-immunoprecipitation of the two proteins, and by fluorescence microscopy, showing co-localization of these proteins in intact cells [20].
• Angiotensinogen, renin, angiotensin-I converting enzyme, and angiotensin II receptor (AT1 and AT2) mRNA expressions were determined by Northern blot and RT-PCR analysis [27].
• In the kidney, renin mRNA was increased up to 10-fold and in situ hybridization showed a marked recruitment of renin-producing cells; however, the levels of angiotensin-I converting enzyme mRNA and AT1 mRNA were not changed [27].
• The study also examined whether AngII would affect RBF in mice lacking AT1A receptors due to gene targeting [19].
• Wild-type cells have a 1.7 ratio of AT1A/AT1B receptor mRNA as determined by semiquantitative reverse transcriptase-polymerase chain reaction [28].

References