Disease relevance of Agtr1a

• Knowledge of the AT1 receptor primary sequence should now permit structural analysis, definition of the angiotensin II receptor gene family and delineation of the contribution of AT receptors to the genetic component of hypertension [1].
• BACKGROUND: The cardiac renin-angiotensin system is activated after myocardial infarction (MI), and both angiotensin AT1 and AT2 receptors are upregulated in the myocardium [2].
• The aim of this study was to investigate the roles of angiotensin II (Ang II) receptor subtypes 1 (AT1) and 2 (AT2) in producing vascular wall hypertrophy and qualitative changes in smooth muscle cell gene expression [3].
• The interaction of ANG II with intrarenal AT1 receptors has been implicated in the progression of diabetic nephropathy, but the role of intrarenal AT2 receptors is unknown [4].
• Thus, we propose that weight loss decreases Ang II-elicited water intake in the female rat by down-regulating the expression of the AT1 receptor [5].

Psychiatry related information on Agtr1a

• Thus, the two AT1 receptor subtypes established to reside in peripheral tissues also are found in the central nervous system where the AT1B subtype may mediate drinking behavior [6].
• Water deprivation upregulates ANG II AT1 binding and mRNA in rat subfornical organ and anterior pituitary [7].
• The reduction in alcohol drinking by peripherally injected angiotensin II is selectively mediated by the AT1 receptor subtype [8].
• Water and sodium depletion and water, NaCl and food deprivation induced sodium appetite, which in the short term depends on cerebral angiotensinergic activity mediated by the activation of AT1 receptors [9].
• Effect of repeated administration of KT3-671, a nonpeptide AT1 receptor antagonist, on diurnal variation in blood pressure, heart rate, and locomotor activity in stroke-prone spontaneously hypertensive rats as determined by radiotelemetry [10].

High impact information on Agtr1a

• All the haemodynamic effects of angiotensin II, including vasoconstriction and adrenal aldosterone release, are mediated through a single class of cell-surface receptors known as AT1 (refs 1, 2) [11].
• AT1 receptors seem to mediate the major cardiovascular effects of angiotensin II [1].
• The renin-angiotensin system (RAS) has been traditionally linked to blood pressure and volume regulation mediated through the angiotensin II (ANG II) type 1 (AT1) receptor [12].
• In rodents, two AT1 receptor subtypes, AT1A and AT1B, have been isolated [13].
• The neuronal expression of AT1A and AT2 receptors was demonstrated in the subfornical organ, the hypothalamus, and the lateral septum [13].

Chemical compound and disease context of Agtr1a

• Therefore, we investigated the effect of AT1 or AT2 subtype receptor chronic blockade by losartan or PD123319 on the vascular hypertrophy in rats with Ang II-induced hypertension [14].
• The goal of this study was to evaluate the contributions of oestrogen and weight loss to isoproterenol (isoprenaline; Iso)-induced Fos immunoreactivity (IR) and to angiotensin type 1 (AT1) receptor mRNA in forebrain regions implicated in the control of fluid balance [5].
• Treatment with the AT1 receptor antagonist losartan for 3 weeks in the 21-day-old rat or for 4 days in the 38-day-old rat resulted in a significant decrease in heart/body weight in both groups and body weight in the 3-week treatment group [15].
• These data indicate that in Wistar rats, a chronic increase in CSF [Na+] may increase hypothalamic aldosterone and activate CNS pathways involving MR, and OLC, leading to increases in AT1-receptor and ACE densities in brain areas involved in cardiovascular regulation and hypertension [16].
• To elucidate the possible involvement of angiotensin II (AII) in the pathogenesis of microvascular changes in severe hypertension, we investigated the effects of angiotensin II type 1 (AT1) receptor antagonist and angiotensin-converting enzyme inhibitor (ACEI) on the expression of adhesion molecules of leukocytes and brain microvessels [17].

Biological context of Agtr1a

• Based on maximum vasoconstriction normalized to 100% ANG II effect in each group, AT1 receptor antagonists produced the same degree of blockade in all groups, with an apparent maximum of 80-90% [18].
• Gene and protein expression of hepatic renin, angiotensinogen, angiotensin-converting enzyme (ACE), and the angiotensin receptors AT1 and AT2 were assessed using real-time reverse-transcription polymerase chain reaction, in vitro autoradiography, and immunohistochemistry [19].
• Our results suggest that astrocyte cultures from neonatal rat brains contain predominantly AT1 receptors that are coupled to a stimulation of inositophospholipid hydrolysis [20].
• The antibody should permit further analysis of endogenous AT1-R phosphorylation in Ang II target cells [21].
• The AT1 receptor is coupled via G proteins to traditional signal transduction mechanisms such as stimulation of phospholipase C, Ca2+ mobilization, and inhibition of adenylate cyclase [22].

Anatomical context of Agtr1a

• The data demonstrate that angiotensin II, via AT1 receptors, can stimulate cardiac fibroblast growth and increase collagen synthesis in cardiac tissue [23].
• AT1 receptors were detected in the placenta at E13 and in the aorta, kidney, lung, liver, and adrenal gland at E19-21, consistent with an adult distribution [24].
• AT-1 receptor mRNA levels decreased 54% (P < .05) only in the myocardium of decompensated rats, whereas AT-2 receptor mRNA did not change in any tissue studied [25].
• These results suggest a predominance of the AT1 receptor subtype in neonatal astrocytes [20].
• In this study, the effects of angiotensin II (AngII) type 1 (AT1) and type 2 (AT2) receptor stimulation on glycosaminoglycan and proteoglycan core protein synthesis in vascular smooth muscle cells (VSMC) were examined [26].

Associations of Agtr1a with chemical compounds

• By using double label in situ hybridization, AT1A receptor expression was localized in corticotropin releasing hormone but not in vasopressin containing neurons in the hypothalamus [13].
• Intrarenal administration of angiotensin II receptor type 1 (AT1) receptor antagonists losartan or EXP-3174 simultaneously with ANG II caused dose-dependent inhibition of ANG II responses [18].
• Little is known about the in vivo contribution of AT1 and AT2 receptor activation to the biological action of Ang II [14].
• The highly abundant angiotensin II receptors were shown to be AT2 by the marked reduction in radioligand binding achieved with PD123177 (10(-7)M), a specific AT2 receptor antagonist, whereas DuP 753 (10(-5)M), an AT1 receptor antagonist, had little effect [24].
• The ability of angiotensin II to stimulate phosphoinositide catabolism and to elevate intracellular calcium concentrations in these cells was blocked by losartan, a specific AT1 receptor antagonist, but not by the AT2 receptor antagonist CGP 42112 [23].

Physical interactions of Agtr1a

• In accordance with previous observations that Tyr4- or Phe8-modified angiotensin II analogs antagonized vasoconstriction mediated exclusively by the AT1 receptor, binding to the AT1 receptor was significantly dependent on Tyr4 or Phe8 of angiotensin II whereas binding to the AT2 receptor was not [27].
• In this study, the mechanism of dynamin-2 action was explored during endocytosis of the G protein-coupled AT1A angiotensin receptor expressed in Chinese hamster ovary cells [28].
• In cardiac myocytes, Stat5 proteins co-immunoprecipitated with the AT1 receptor [29].
• Competition experiments with synthetic peptides suggest that each of the YIPP amino acids, including tyrosine 319, is important in Jak2 binding to the AT1A receptor [30].
• Assessment of Ang II receptors by 125I-[Sar1Thr8]-Ang II binding showed that the AT1-receptor subtype predominates in the ganglia [31].

Enzymatic interactions of Agtr1a

• The PLCgamma1-AT1 receptor interaction appears to depend on phosphorylation of tyrosine 319 in a YIPP motif in the C-terminal intracellular domain of the AT1 receptor and binding of the phosphorylated receptor by the most C-terminal of two Src homology 2 domains in PLCgamma1 [32].

Regulatory relationships of Agtr1a

• AT2 blockade potentiates angiotensin-induced PGE2 production at the AT1 receptor [33].
• Treatment of AT1 receptor-expressing VSMC with AngII resulted in a dose-dependent and time-dependent increase (2- to 4-fold) in (3)H-glucosamine/(35)S-sulfate incorporation, which was abolished by pretreatment with the AT1 receptor antagonist, losartan [26].
• A centrally acting, anxiolytic angiotensin II AT1 receptor antagonist prevents the isolation stress-induced decrease in cortical CRF1 receptor and benzodiazepine binding [34].
• Smad2 activation was inhibited by AT1 receptor blockade but was unaltered by TYR [35].
• AT1A subtype mRNA was expressed in vascular smooth muscle whereas AT1B mRNA was expressed in adrenal and pituitary [6].

Other interactions of Agtr1a

• CONCLUSION: In DS hypertensive rats, some of the renoprotective effects of AT1 receptor blockade are accompanied by reductions in intrarenal Ang II contents and MAPK activity, which might not be mediated through arterial pressure changes [36].
• Angiotensin II (Ang II) interaction with the neuronal AT1 receptor results in a chronic stimulation of neuromodulation that involves the expression of norepinephrine transporter (NET) and tyrosine hydroxylase (TH) [37].
• Our results implicate a modulation of upstream neurotransmission processes regulating cortical CRF1 receptors and the GABA(A) complex as molecular mechanisms responsible for the anti-anxiety effect of centrally acting AT1 receptor antagonists [34].
• Myocardial ERK activation did not depend on AT1 receptor signaling as it was not affected by AT1 receptor blockade [35].
• For endothelial cells, we examined the expression of intercellular adhesion molecule-1 (ICAM-1), the AT1 receptor, and glucose transporter-1 (GLUT-1, a marker of the blood-brain barrier) using reverse transcription-polymerase chain reaction (RT-PCR) [17].

Analytical, diagnostic and therapeutic context of Agtr1a

• Distribution of AT1 and AT2 receptors was determined by competition with losartan and PD123177, respectively, and the density of the receptors was quantified by emulsion autoradiography [38].
• To evaluate receptor subtype mediation, responses were compared in mice with or without the AT1A receptor (deleted by gene targeting) [39].
• Western blot analysis showed that AT1 protein levels in the kidney and liver were also similar in the two groups [40].
• Adrenal AT1A mRNA, determined by Northern blot analysis, was increased in LS (P<.05) but not in NS+prazosin (P>.05), compared with NS [41].
• Immunohistochemistry revealed that this increased AT1 receptor labeling occurred mainly in vascular smooth muscle layer of intrarenal blood vessels including afferent and efferent arterioles, juxtaglomerular apparatus, glomerular mesangial cells, proximal tubular cells, and renomedullary interstitial cells (RMICs) in the transgenic rats [42].

References