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Gene Review

Agtr2  -  angiotensin II receptor, type 2

Mus musculus

Synonyms: AI316812, AT2, AT2 receptor, AW107640, Angiotensin II type-2 receptor, ...
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Disease relevance of Agtr2

  • Accordingly, LV/body weight ratios (3.7+/-0.2 versus 3.0+/-0.1 on day 14) and LV end-diastolic (4.8+/-0.3 versus 3.9+/-0.4 mm on day 7) and end-systolic (4.4+/-0.3 versus 3.2+/-0.6 mm on day 7) dimensions evaluated by echocardiography were significantly greater in Agtr2- than in Agtr2+ mice [1].
  • To examine the in vivo role of this receptor in vascular diseases, we developed a mouse model of vascular remodeling and compared the responses in wild-type (Agtr2(+)) and AT(2) receptor knockout (Agtr2(-)) mice [2].
  • METHODS AND RESULTS: In Agtr2+ (wild-type) mice, MCA occlusion induced focal ischemia of approximately 20% to 30% of the total area in coronal section of the brain [3].
  • Despite up-regulation of the AT2 receptor, we found no support for an effect of the AT2 receptor on atherogenesis in this model [4].
  • Sustained hypersensitivity to angiotensin II and its mechanism in mice lacking the subtype-2 (AT2) angiotensin receptor [5].

Psychiatry related information on Agtr2


High impact information on Agtr2

  • 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 [9].
  • Thus, although the AT2 receptor is not required for embryonic development, it plays a role in the central nervous system and cardiovascular functions that are mediated by the renin-angiotensin system [9].
  • Here we report the unexpected finding that the targeted disruption of the mouse AT2 gene resulted in a significant increase in blood pressure and increased sensitivity to the pressor action of angiotensin II [10].
  • Our results show that angiotensin II activates AT1 and AT2, which have mutually counteracting haemodynamic effects, and that AT2 regulates central nervous system functions, including behaviour [10].
  • In addition, disruption of the AT2 gene attenuated exploratory behaviour and lowered body temperature [10].

Chemical compound and disease context of Agtr2


Biological context of Agtr2


Anatomical context of Agtr2

  • Collectively, Agtr1 or Agtr2 null mutant mice suffer from urinary tract obstruction [18].
  • Vascular injury was induced by polyethylene cuff placement around the femoral artery of wild-type (Agtr2+) and Agtr2- mice [17].
  • Myocyte cross-sectional areas were increased after MI, but the magnitudes were similar in Agtr2+ and Agtr2- mice, indicating the greater increases in LV dimensions and weight in Agtr2- mice are due to elongation of myocyte length and/or an increase in the interstitial weight (including vasculatures, infiltrated cells, and interstitial fluid) [1].
  • Angiotensin II type 2 (AT2) receptor is abundantly expressed in vascular smooth muscle cells (VSMC) of the fetal vasculature during late gestation (embryonic day 15-20), during which the blood vessels undergo remodeling [15].
  • Angiotensin II type 2 (AT2) receptor is abundantly and widely expressed in fetal tissues but present only in restricted tissues in the adult such as brain and atretic ovary [19].

Associations of Agtr2 with chemical compounds

  • These inhibitory actions of valsartan were weaker in Agtr2- mice [3].
  • Reduced growth, abnormal kidney structure, and type 2 (AT2) angiotensin receptor-mediated blood pressure regulation in mice lacking both AT1A and AT1B receptors for angiotensin II [20].
  • The AT2 receptor ligands PD-123319 and CGP-42112 do not alter Ang II effects in either VSMC type, suggesting a paucity of AT2 receptors and/or an absence of their linkage to [Ca2+]i pathways [21].
  • In wild-type fibroblasts, Ang II increased collagen synthesis accompanied by an increase in expression of tissue inhibitor of metalloproteinase (TIMP)-1, and these increases were inhibited by valsartan, an AT1 receptor blocker, but augmented by PD123319, an AT2 receptor antagonist [22].
  • OBJECTIVE: Previous studies have suggested that activation of angiotensin II (ANG II) type 2 (AT2) receptors results in nitric oxide (NO) release via activation of endothelial bradykinin B2 (B2R) receptors [23].

Physical interactions of Agtr2


Regulatory relationships of Agtr2

  • Taken together, these results suggest that increased IRF-1 after serum starvation contributes to the induction of apoptosis and that increased IRF-1 up-regulates the AT2 receptor expression after serum starvation, resulting in enhanced angiotensin II-mediated apoptosis [24].
  • Angiotensin AT2 receptors directly stimulate renal nitric oxide in bradykinin B2-receptor-null mice [27].
  • Inhibition of AT2 receptors with PD123319 reduced significantly flow-induced dilation in TK+/+ mice, but had no significant effect in TK-/- mice [28].
  • Since AT1 receptors are upregulated in AT2 -/y mice kidneys, NO-dependent effects were greater in these mice [29].
  • Superoxide production and NADPH oxidase activity were enhanced in the ischemic area of the brain in Agtr2- mice [3].

Other interactions of Agtr2


Analytical, diagnostic and therapeutic context of Agtr2


  1. Cardioprotective role of AT2 receptor in postinfarction left ventricular remodeling. Oishi, Y., Ozono, R., Yano, Y., Teranishi, Y., Akishita, M., Horiuchi, M., Oshima, T., Kambe, M. Hypertension (2003) [Pubmed]
  2. Inflammation influences vascular remodeling through AT2 receptor expression and signaling. Akishita, M., Horiuchi, M., Yamada, H., Zhang, L., Shirakami, G., Tamura, K., Ouchi, Y., Dzau, V.J. Physiol. Genomics (2000) [Pubmed]
  3. Possible inhibition of focal cerebral ischemia by angiotensin II type 2 receptor stimulation. Iwai, M., Liu, H.W., Chen, R., Ide, A., Okamoto, S., Hata, R., Sakanaka, M., Shiuchi, T., Horiuchi, M. Circulation (2004) [Pubmed]
  4. Angiotensin II, type 2 receptor is not involved in the angiotensin II-mediated pro-atherogenic process in ApoE-/- mice. Johansson, M.E., Wickman, A., Fitzgerald, S.M., Gan, L.M., Bergström, G. J. Hypertens. (2005) [Pubmed]
  5. Sustained hypersensitivity to angiotensin II and its mechanism in mice lacking the subtype-2 (AT2) angiotensin receptor. Siragy, H.M., Inagami, T., Ichiki, T., Carey, R.M. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  6. Central angiotensin II controls alcohol consumption via its AT1 receptor. Maul, B., Krause, W., Pankow, K., Becker, M., Gembardt, F., Alenina, N., Walther, T., Bader, M., Siems, W.E. FASEB J. (2005) [Pubmed]
  7. Effects of targeted disruption of the mouse angiotensin II type 2 receptor gene on stress-induced hyperthermia. Watanabe, T., Hashimoto, M., Okuyama, S., Inagami, T., Nakamura, S. J. Physiol. (Lond.) (1999) [Pubmed]
  8. Pain threshold, learning and formation of brain edema in mice lacking the angiotensin II type 2 receptor. Sakagawa, T., Okuyama, S., Kawashima, N., Hozumi, S., Nakagawasai, O., Tadano, T., Kisara, K., Ichiki, T., Inagami, T. Life Sci. (2000) [Pubmed]
  9. Behavioural and cardiovascular effects of disrupting the angiotensin II type-2 receptor in mice. Hein, L., Barsh, G.S., Pratt, R.E., Dzau, V.J., Kobilka, B.K. Nature (1995) [Pubmed]
  10. Effects on blood pressure and exploratory behaviour of mice lacking angiotensin II type-2 receptor. Ichiki, T., Labosky, P.A., Shiota, C., Okuyama, S., Imagawa, Y., Fogo, A., Niimura, F., Ichikawa, I., Hogan, B.L., Inagami, T. Nature (1995) [Pubmed]
  11. Cardiac hypertrophy and fibrosis in chronic L-NAME-treated AT2 receptor-deficient mice. Gross, V., Obst, M., Kiss, E., Janke, J., Mazak, I., Shagdarsuren, E., Müller, D.N., Langenickel, T.H., Gröne, H.J., Luft, F.C. J. Hypertens. (2004) [Pubmed]
  12. Heterogeneity of angiotensin II AT2 receptors in the rat brain. Tsutsumi, K., Saavedra, J.M. Mol. Pharmacol. (1992) [Pubmed]
  13. Cloning, expression and regulation of angiotensin II receptors. Inagami, T., Iwai, N., Sasaki, K., Yamano, Y., Bardhan, S., Chaki, S., Guo, D.F., Furuta, H., Ohyama, K., Kambayashi, Y. Eur. Heart J. (1994) [Pubmed]
  14. Angiotensin II AT2 receptors are functionally coupled to protein tyrosine dephosphorylation in N1E-115 neuroblastoma cells. Nahmias, C., Cazaubon, S.M., Briend-Sutren, M.M., Lazard, D., Villageois, P., Strosberg, A.D. Biochem. J. (1995) [Pubmed]
  15. Expression of the AT2 receptor developmentally programs extracellular signal-regulated kinase activity and influences fetal vascular growth. Akishita, M., Ito, M., Lehtonen, J.Y., Daviet, L., Dzau, V.J., Horiuchi, M. J. Clin. Invest. (1999) [Pubmed]
  16. Linkage mapping of the angiotensin AT2 receptor gene (Agtr2) to the mouse X chromosome. Hein, L., Dzau, V.J., Barsh, G.S. Genomics (1995) [Pubmed]
  17. Sex difference in vascular injury and the vasoprotective effect of valsartan are related to differential AT2 receptor expression. Okumura, M., Iwai, M., Ide, A., Mogi, M., Ito, M., Horiuchi, M. Hypertension (2005) [Pubmed]
  18. Role of angiotensin in the development of the kidney and urinary tract. Pope, J.C., Nishimura, H., Ichikawa, I. Néphrologie. (1998) [Pubmed]
  19. The growth-dependent expression of angiotensin II type 2 receptor is regulated by transcription factors interferon regulatory factor-1 and -2. Horiuchi, M., Koike, G., Yamada, T., Mukoyama, M., Nakajima, M., Dzau, V.J. J. Biol. Chem. (1995) [Pubmed]
  20. Reduced growth, abnormal kidney structure, and type 2 (AT2) angiotensin receptor-mediated blood pressure regulation in mice lacking both AT1A and AT1B receptors for angiotensin II. Oliverio, M.I., Kim, H.S., Ito, M., Le, T., Audoly, L., Best, C.F., Hiller, S., Kluckman, K., Maeda, N., Smithies, O., Coffman, T.M. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  21. Angiotensin AT1B receptor mediates calcium signaling in vascular smooth muscle cells of AT1A receptor-deficient mice. Zhu, Z., Zhang, S.H., Wagner, C., Kurtz, A., Maeda, N., Coffman, T., Arendshorst, W.J. Hypertension (1998) [Pubmed]
  22. Regulation of collagen synthesis in mouse skin fibroblasts by distinct angiotensin II receptor subtypes. Min, L.J., Cui, T.X., Yahata, Y., Yamasaki, K., Shiuchi, T., Liu, H.W., Chen, R., Li, J.M., Okumura, M., Jinno, T., Wu, L., Iwai, M., Nahmias, C., Hashimoto, K., Horiuchi, M. Endocrinology (2004) [Pubmed]
  23. Genetic inactivation of the B2 receptor in mice worsens two-kidney, one-clip hypertension: role of NO and the AT2 receptor. Cervenka, L., Vanecková, I., Malý, J., Horácek, V., El-Dahr, S.S. J. Hypertens. (2003) [Pubmed]
  24. Interferon regulatory factor-1 up-regulates angiotensin II type 2 receptor and induces apoptosis. Horiuchi, M., Yamada, T., Hayashida, W., Dzau, V.J. J. Biol. Chem. (1997) [Pubmed]
  25. Changes in angiotensin II receptors in dopamine-rich regions of the mouse brain with age and ethanol consumption. Daubert, D.L., Meadows, G.G., Wang, J.H., Sanchez, P.J., Speth, R.C. Brain Res. (1999) [Pubmed]
  26. Stimulation of different subtypes of angiotensin II receptors, AT1 and AT2 receptors, regulates STAT activation by negative crosstalk. Horiuchi, M., Hayashida, W., Akishita, M., Tamura, K., Daviet, L., Lehtonen, J.Y., Dzau, V.J. Circ. Res. (1999) [Pubmed]
  27. Angiotensin AT2 receptors directly stimulate renal nitric oxide in bradykinin B2-receptor-null mice. Abadir, P.M., Carey, R.M., Siragy, H.M. Hypertension (2003) [Pubmed]
  28. Flow-dependent dilation mediated by endogenous kinins requires angiotensin AT2 receptors. Bergaya, S., Hilgers, R.H., Meneton, P., Dong, Y., Bloch-Faure, M., Inagami, T., Alhenc-Gelas, F., Lévy, B.I., Boulanger, C.M. Circ. Res. (2004) [Pubmed]
  29. Angiotensin II modulates renal sympathetic neurotransmission through nitric oxide in AT2 receptor knockout mice. Stegbauer, J., Vonend, O., Habbel, S., Quack, I., Sellin, L., Gross, V., Rump, L.C. J. Hypertens. (2005) [Pubmed]
  30. AT2 receptor and vascular smooth muscle cell differentiation in vascular development. Yamada, H., Akishita, M., Ito, M., Tamura, K., Daviet, L., Lehtonen, J.Y., Dzau, V.J., Horiuchi, M. Hypertension (1999) [Pubmed]
  31. Stimulation of cyclic GMP production via AT2 and B2 receptors in the pressure-overloaded aorta after banding. Hiyoshi, H., Yayama, K., Takano, M., Okamoto, H. Hypertension (2004) [Pubmed]
  32. Angiotensin II receptor types 1A, 1B, and 2 in murine neuroblastoma Neuro-2a cells. Hoffmann, A., Cool, D.R. J. Recept. Signal Transduct. Res. (2003) [Pubmed]
  33. Inhibition of pressure natriuresis in mice lacking the AT2 receptor. Gross, V., Schunck, W.H., Honeck, H., Milia, A.F., Kärgel, E., Walther, T., Bader, M., Inagami, T., Schneider, W., Luft, F.C. Kidney Int. (2000) [Pubmed]
  34. Affinity purification of angiotensin type 2 receptors from N1E-115 cells: evidence for agonist-induced formation of multimeric complexes. Siemens, I.R., Yee, D.K., Reagan, L.P., Fluharty, S.J. J. Neurochem. (1994) [Pubmed]
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