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Angiotensin II Receptors AT1 and AT2: New Mechanisms of Signaling And Antagonistic Effects of AT1 and AT2

  • Tadashi Inagami
  • Satoru Eguchi
  • Satoshi Tsuzuki
  • Toshihiro Ichiki
Part of the Progress in Experimental Cardiology book series (PREC, volume 2)

Summary

A series of pharmaceutical successes in the treatment of not only essential hypertension but also vascular hypertrophic and hyperplastic diseases, congestive heart failure, and renal degenerative diseases, with angiotensin-converting enzyme inhibitors and angiotensin (Ang) II receptor antagonists indicates that angiotensin may play a pivotal role in the genesis and maintenance of high blood pressure and resultant stroke, atherosclerosis, and heart and kidney diseases. There is more than one form of Ang II receptors. Using expression cloning, we isolated the AT1 cDNA from bovine adrenocortical cells from the kidney of spontaneously hypertensive rats and AT2 cDNA from rat PC12W cells and we showed that it was not the mas oncogene product. Further, we showed that in rodents, AT1 consists of two subtypes, AT1a and AT1b, which share a high degree of sequence homology in their coding regions, although mechanisms of their respective transcriptional control seemed to be different. By computer-assisted modeling and site-directed mutagenesis, we have delineated the docking site of Ang II. AT1a (and AT1b) serves most of the commonly recognized actions of Ang II. In addition, this G protein-coupled receptor (GPCR) also activates a tyrosine kinase mechanism that may be an underlying cause of Ang II-mediated hypertrophic and hyperplastic changes of cardiovascular tissues. In the vascular system, the phospholipase C (PLC) activated by Ang II seems to be PLC-β rather than PLC-γ1.

Interestingly, we found that Gq-activated PLC-β activates p21 ras and mitogen-activated protein kinase (MAPK) in rat vascular smooth muscle cells. The mechanism of the crosstalk between AT1 and the tyrosine kinase system is triggered by Ca2+, but does not involve protein kinase C.

Studies using targeted gene deletion indicated that Ang II is intimately involved in nephrogenesis. Mice lacking angiotensinogen showed an abnormality in the formation of renal papilla, retardation in glomerular maturation, marked hypertrophy of small arteries of the kidney, and tubular dilatation, whereas targeted deletion of the AT1 receptor resulted in small arterial wall hypertrophy. Blood pressure of AT1A-deleted mice was markedly reduced (-45 mmHg).

The role and mechanism of action of AT2 was not clear. We have recently produced AT2 gene null mice and AT1a knockout mice by targeted gene deletion. AT2-deleted mice had a higher blood pressure, whereas AT1-deleted mice showed lower blood pressure. Deletion of the AT2 gene also showed reduced exploratory activity. The most conspicuous action of the AT2 receptor is seen in its salt-retaining action in the renal tubule. Under a constant renal blood flow condition an AT2 antagonist markedly increased the urine volume and concomitant natriuresis. These effects are completely abolished in AT2 deleted mice. The molecular and cell biological studies of the angiotensin receptors are needed.

Despite the complexity and often mutually antagonistic actions of AT1 and AT2, Ang II, working through AT1 and AT2 of the kidney work in the same direction to retain salt and water. These observations, as well as the effects of Ang II, indicate that the most fundamental role of Ang II is its role in the development of the salt-retaining organ, the kidney, and Ang II is uniquely related to the kidney in that both AT1 and AT2 receptors work for the retention of salt.

Keywords

Vascular Smooth Muscle Cell Target Gene Deletion Angiotensin Blockade Bovine Adrenocortical Cell Vascular Smooth Muscle Cell Hypertrophy 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. 1.
    Timmermans PBMWM, Wong PC, Chili AT, Herblin WF, Benefield P, Carini DJ, Lee RJ, Wexler RR, Saye JAM, Smith RD. 1993. Angiotensin II receptors and angiotensin II receptor antagonist. Pharmacological Rev 45:205–251.Google Scholar
  2. 2.
    Inagami T, Guo D-F, Kitami Y. 1994. Molecular biology of angiotensin II receptors: Overview. J Hypertens 12:(Suppl 10):S83–S94.Google Scholar
  3. 3.
    Iwai N, Inagami T. 1992. Identification of two subtypes in the rat type 1 angiotensin II receptor. FEBS Lett 298:257–260.PubMedCrossRefGoogle Scholar
  4. 4.
    Sandberg K, Ji H, Clark AJ, Shapira H, Catt KJ. 1992. Cloning and expression of a novel angiotensin II receptor subtype. J Biol Chem 267:9455–9458.PubMedGoogle Scholar
  5. 5.
    Kakar SS, Sellers JC, Devor DC, Musgrove LC, Neil JD. 1992. Angiotensin II type-a receptor subtype cDNAs: differential tissue expression and hormonal regulation. Biochem Biophys Res Commun 183:1090–1096.PubMedCrossRefGoogle Scholar
  6. 6.
    Elton TS, Stephan CC, Taylor GR, Kimball MG, Martin MM, Durand JN, et al. 1992. Isolation of two distinct type 1 angiotensin II receptor genes. Biochem Biophys Res Commun 184:1067–1073.PubMedCrossRefGoogle Scholar
  7. 7.
    Saavedra JM. 1992. Brain and pituitary angiotensin. Endocrine Rev 13:324–380.Google Scholar
  8. 8.
    Bottari SP, de Gasparo M, Steckerings UM, Leven NR. 1993. Angiotensin II receptor subtypes: characterization, signaling mechanisms, and possible physiological implications. Frontiers in Neuroendocrinol 14:123–171.CrossRefGoogle Scholar
  9. 9.
    Dudley DT, Hubbell SE, Summerfeit RM. 1991. Characterization of angiotensin II (AT2) binding sites in R3T3 cells. Mol Pharmacol 40:360–367.PubMedGoogle Scholar
  10. 10.
    Speth RC, Kim KH. 1990. Discrimination of two angiotensin II receptor subtypes with a selective agonist analogue of angiotensin II p-aminophenylalanine8 angiotensin II. Biochem Biophys Res Commun 169:997–1006.PubMedCrossRefGoogle Scholar
  11. 11.
    Darimont C, Vassaux G, Alhand G, Negrel R. 1994. Differentiation of preadipose cells: paracrine role of prostacyclin upon stimulation of adipose cells by angiotensin II. Endocrinology 135:2030–2036.PubMedCrossRefGoogle Scholar
  12. 12.
    Buisson B, Bottari SP, de Gasparo M, Gallet-Payet N, Paget MD. 1992. The angiotensin AT2 receptor modulates T-type calcium current in non-differentiated NG108 cells. FEBS Lett 309:161–164.PubMedCrossRefGoogle Scholar
  13. 13.
    Reagan LP, Ye XH, Mir R, De Palo LR, Fluherty SJ. 1990. Up-regulation of angiotensin II receptors by in vitro differentiation of murine N1E-115 neuroblastoma cells. Mol Pharmacol 38:878–886.PubMedGoogle Scholar
  14. 14.
    Chappell MD, Jacobsen DW, Tallant EA. 1995. Characterization of angiotensin II receptor subtypes in pancreatic acinar AR42J cells. Peptides 16:741–747.PubMedCrossRefGoogle Scholar
  15. 15.
    Kambayashi Y, Bardhan S, Inagami T. 1993. Peptide growth factors markedly decrease the ligand binding of angiotensin II type 2 receptor in rat cultured vascular smooth muscle cells. Biochem Biophys Res Commun 194:478–482.PubMedCrossRefGoogle Scholar
  16. 16.
    van Biesen T, Luttrell LM, Hawes BE, Lefkowitz RJ. 1996. Mitogen signaling via G protein-coupled receptors. Endocrine Rev 17:698–714.Google Scholar
  17. 17.
    Morrero MB, Paxton WG, Duff JL, Berk BC, Bernstein KE. 1994. Angiotensin II stimulates tyrosine phosphorylation of phospholipase Cγ1 in vascular smooth muscle cells. J Biol Chem 269:10935–10939.Google Scholar
  18. 18.
    Morrero MB, Schieffer B, Paxton WG, Schieffer E, Bernstein KE. 1995. Electroporation of pp60C-src antibodies inhibits the angiotensin II activation of phospholipase C-γ1 in rat aortic smooth muscle cells. J Biol Chem 270:15734–15738.CrossRefGoogle Scholar
  19. 19.
    Ishida M, Marrero MB, Schieffer B, Ishida T, Bernstein KE, Berk BC. 1993. Angiotensin II activates pp60C-src in vascular smooth muscle cells. Circ Res 77:1053–1059.CrossRefGoogle Scholar
  20. 20.
    Eguchi S, Matsumoto T, Motley E, Utsunomiya H, Inagami T. 1996. Identification of an essential signaling cascade for mitogen-activated kinase activation by angiotensin II in cultured rat vascular smooth muscle cells. J Biol Chem 271:14169–14175.PubMedCrossRefGoogle Scholar
  21. 21.
    Lettrell LM, Hawes BE, van Biesen T, Lettrell DK, Lansing TJ, Lefkowitz RJ. 1996. Role of c-Src tyrosine kinase in G protein-coupled receptor-and βγ subunit-mediated activation of mitogen-activated protein kinase. J Biol Chem 271:19443–19450.CrossRefGoogle Scholar
  22. 22.
    Bottari SP, King IN, Reichlin S, Dahlstroem I, Lydon N, de Gasparo M. 1992. The angiotensin AT2 receptor stimulates protein tyrosine phosphatase activity and mediates inhibition of particulate guanylate cyclase. Biochem Biophys Res Commun 183:206–211.PubMedCrossRefGoogle Scholar
  23. 23.
    Kambayashi Y, Bardhan S, Takahashi K, Tsuzuki S, Inui H, Hamakubo T, Inagami T. 1993. Molecular cloning of a novel angiotensin II receptor isoform involved in phosphotyrosine phosphatase inhibition. J Biol Chem 268:24543–24546.PubMedGoogle Scholar
  24. 24.
    Tsuzuki S, Eguchi S, Inagami T. 1996. Inhibition of cell proliferation and activation of protein tyrosine phosphatase mediated by angiotensin II type 2 (AT2) receptor in R3T3 cells. Biochem Biophys Res Commun 228:825–830.PubMedCrossRefGoogle Scholar
  25. 25.
    Tsuzuki S, Matoba T, Eguchi S, Inagami T. 1996. Angiotensin II type 2 receptor inhibits cell proliferation and activates tyrosine phosphatase. Hypertension 28:916–918.PubMedCrossRefGoogle Scholar
  26. 26.
    Geisterifer AA, Peach MJ, Owens GK. 1988. Angiotensin II induces hypertrophy not hyperplasia, of cultured rat aortic smooth muscle cells. Circ Res 62:749–756.CrossRefGoogle Scholar
  27. 27.
    Gibbons GH, Pratt RE, Dzau VJ. 1992. Vascular smooth muscle cell hypertrophy vs hyperplasia. Autocrine transforming growth factor-beta 1 expression determines growth response to angiotensin II. J Clin Invest 90:456–461.PubMedCrossRefGoogle Scholar
  28. 28.
    Weber H, Taylor DS, Molloy CJ. 1994. Angiotensin II induces delayed mitogenesis and cellular proliferation in rat aortic smooth muscle cells. Correlation with the expression of specific endogenous growth factors and reversal by surnamin. J Clin Invest 93:788–798.PubMedCrossRefGoogle Scholar
  29. 29.
    Nakajima M, Hutchinson HG, Fujinaga M, Hayashida W, Morishita R, Zhang L, Horiuchi M, Pratt R, Dzau VJ. 1995. The angiotensin II (AT2) receptor antagonizes the growth effects of the AT1 receptor: gain-of-function study using gene transfer. Proc Natl Acad Sci USA 92:10663–10667.PubMedCrossRefGoogle Scholar
  30. 30.
    Janiak P, Pillan A, Prost J-T, Vilaine J-P. 1992. Role of angiotensin subtype 2 receptor in neointima formation after vascular injury. Hypertension 20:737–745.PubMedCrossRefGoogle Scholar
  31. 31.
    Viswanathan M, Seltzer A, Saavedra JM. 1994. Heterogeneous expression of angiotensin II AT2 receptor in neointima of rat carotid artery and aorta after balloon catheter injury. Peptides 15:1205–1212.PubMedCrossRefGoogle Scholar
  32. 32.
    Yamada T, Horiuchi M, Dzau VJ. 1996. Angiotensin II type 2 receptor mediates programmed cell death. Proc Acad Sci USA 93:156–160.CrossRefGoogle Scholar
  33. 33.
    Hayashida W, Horiuchi M, Dzau VJ. 1996. Intracellular third loop domain of angiotensin II type-2 receptor: Role in mediating signal transduction and cellular function. J Biol Chem 271:21985–21992.PubMedCrossRefGoogle Scholar
  34. 34.
    Zhang J, Pratt RE. 1996. The AT2 receptor selectively associates with Giα2 and Giα3 in the rat fetus. J Biol Chem 271:15026–15033.PubMedCrossRefGoogle Scholar
  35. 35.
    Ichiki T, Labosky PA, Shiota C, Okuyama S, Imagawa Y, Fogo A, Niimura F, Ichikawa I, Hogan BLM, Inagami T. 1995. Effects on blood pressure and reduced exploratory behavior in mice lacking angiotensin II type 2 receptor. Nature 377:748–750.PubMedCrossRefGoogle Scholar
  36. 36.
    Hein L, Barsk GS, Pratt RE, Dzau VJ, Kobilka BK. 1995. Behavioral and cardiovascular effects of disruption the angiotensin II type-2 receptor gene in mice. Nature 377:744–747.PubMedCrossRefGoogle Scholar
  37. 37.
    Ito M, Oliverio MI, Mannon PJ, Best CF, Maeda N, Smithies O, Coffinan TM. 1995. Regulation of blood pressure by the type 1A angiotensin II receptor gene. Proc Natl Acad Sci USA 92:3521–3525.PubMedCrossRefGoogle Scholar
  38. 38.
    Sugaya T, Nishimatsu S-I, Tanimoto K, Takimoto E, Yamagishi T, Imamura K, Goto S, Imaizumi K, Hisada Y, Otsuka A, Uchida H, Sugiura M, Fukuta K, Fukamizu A, Murakami K. 1995. Angiotensin II type la receptor-deficient mice with hypotension and hyperreninemia. J Biol Chem 2709:18719–18722.Google Scholar
  39. 39.
    Tanimoto K, Sugiyama F, Goto Y, Ishida J, Takimoto E, Yagami K-I, Fukamizu A, Murakami K. 1994. J Biol Chem 269:31334–31337.PubMedGoogle Scholar
  40. 40.
    Kim H-S, Krege JH, Kluckman KD, Hagaman JR, Hodgin JB, Best CF, Jennett JC, Coffman TM, Maeda N, Smithies O. 1995. Genetic control of blood pressure and the angiotensinogen locus. Proc Natl Acad Sci USA 92:2735–2739.PubMedCrossRefGoogle Scholar
  41. 41.
    Keiser JA, Bjork FA, Hodges JC, Taylor DG Jr. 1992. Renal hemodynamic and excretory responses to PD123319 and losartan, nonpeptide AT1 and AT2 subtype-specific angiotensin II ligands. J Pharm Exptl Ther 263:1154–1160.Google Scholar
  42. 42.
    Roman RJ, Cowley AW Jr. 1985. Characterization of a new model for the study of pressure natriuresis in the rat. Am J Physiol 248:F190–F198.PubMedGoogle Scholar
  43. 43.
    Lo M, Liu KL, Lanteime P, Sassard J. 1995. Subtype 2 of angiotensin II receptors controls pressure natriuresis in rats. J Clin Invest 95:1394–1397.PubMedCrossRefGoogle Scholar
  44. 44.
    Siragy HM, Carey RM. 1996. The subtype-2 (AT2) angiotensin receptor regulates renal cyclic guanosine 3′, 5′-mono-phosphate and AT1 receptor mediated prostaglandin E2 production in conscious rats. J Clin Invest 97:1978–1982.PubMedCrossRefGoogle Scholar
  45. 45.
    Sumners C, Myers LM. 1991. Angiotensin II decreases cGMP levels in neuronal cultures from rat brain. Am J Physiol 260:C79–C87.PubMedGoogle Scholar
  46. 46.
    Tsutsumi K, Saavedra JM. 1991. Characterization and development of angiotensin II receptor subtypes (AT1 and AT2) in rat brain. Am J Physiol 261:R209–R216.PubMedGoogle Scholar
  47. 47.
    Song K, Allen AM, Paxinos G, Mendelsohn FAA. 1992. Mapping of angiotensin II receptor subtype heterogeneity in rat brain. J Comp Neurol 316:467–484.PubMedCrossRefGoogle Scholar
  48. 48.
    Levy BI, Benessiano J, Henrion D, Caputo L, Heymes C, Durier M, Poitevin P, Samuel JL. 1996. Chronic blockage of AT2-subtype receptors prevents the effect of angiotensin II on the rat ventricular structure. J Clin Invest 98:418–425.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1998

Authors and Affiliations

  • Tadashi Inagami
    • 1
  • Satoru Eguchi
    • 1
  • Satoshi Tsuzuki
    • 1
  • Toshihiro Ichiki
    • 1
  1. 1.Vanderbilt University School of MedicineNashvilleUSA

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