Digestive Diseases and Sciences

, Volume 50, Issue 5, pp 942–948 | Cite as

Angiotensin II Participates in Hepatic Inflammation and Fibrosis through MCP-1 Expression

  • Keishi Kanno
  • Susumu TazumaEmail author
  • Tomoji Nishioka
  • Hideyuki Hyogo
  • Kazuaki Chayama


In this study, we assessed the hypothesis that angiotensin (Ang) II could modulate inflammatory cell recruitment into the liver through hepatic expression of monocyte chemoattractant protein (MCP)-1 during liver injury. For in vivo study, Ang II type 1a knockout (AT1a KO) mice and wild-type (WT) mice were treated with CCl4 for 4 weeks. After CCl4 treatment, AT1a KO mice showed lower expression of MCP-1 and fewer CD68-positive cells in the liver compared with WT mice. For in vitro study, Ang II was added to LI90 cells. Ang II enhanced MCP-1 mRNA together with RhoA mRNA and also induced secretion of MCP-1 into the culture medium. This change was strongly blocked by Y-27632, a specific Rho-kinase inhibitor. These results suggest that Ang II modulates hepatic inflammation via production of MCP-1 by hepatic stellate cells, and the effect of Ang II on MCP-1 production is, at least partly, mediated by the Rho/Rho-kinase pathway.

Key Words

renin–angiotensin system monocyte chemoattractant protein-1 hepatic stellate cell hepatic inflammation hepatic fibrosis angiotensin II type 1a knockout mouse small G protein Rho/Rho-kinase pathway carbon tetrachloride 


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  1. 1.
    Bataller R, Gines P, Nicolas JM, Gorbig MN, Garcia-Ramallo E, Gasull X, Bosch J, Arroyo V, Rodes J: Angiotensin II induces contraction and proliferation of human hepatic stellate cells. Gastroenterology 118:1149–1156, 2000PubMedGoogle Scholar
  2. 2.
    Wei HS, Li DG, Lu HM, Zhan YT, Wang ZR, Huang X, Zhang J, Cheng JL, Xu QF: Effects of AT1 receptor antagonist, losartan, on rat hepatic fibrosis induced by CCl 1(4). World J Gastroenterol 6:540–545, 2000PubMedGoogle Scholar
  3. 3.
    Jonsson JR, Clouston AD, Ando Y, Kelemen LI, Horn MJ, Adamson MD, Purdie DM, Powell EE: Angiotensin-converting enzyme inhibition attenuates the progression of rat hepatic fibrosis. Gastroenterology 121:148–155, 2001PubMedGoogle Scholar
  4. 4.
    Yoshiji H, Kuriyama S, Yoshii J, Ikenaka Y, Noguchi R, Nakatani T, Tsujinoue H, Fukui H: Angiotensin-II type 1 receptor interaction is a major regulator for liver fibrosis development in rats. Hepatology 34:745–750, 2001PubMedGoogle Scholar
  5. 5.
    Kanno K, Tazuma S, Chayama K: AT1A-deficient mice show less severe progression of liver fibrosis induced by CCl (4). Biochem Biophys Res Commun 308:177–183, 2003PubMedGoogle Scholar
  6. 6.
    Paizis G, Cooper ME, Schembri JM, Tikellis C, Burrell LM, Angus PW: Up-regulation of components of the renin-angiotensin system in the bile duct-ligated rat liver. Gastroenterology 123:1667–1676, 2002PubMedGoogle Scholar
  7. 7.
    Bataller R, Sancho-Bru P, Gines P, Lora JM, Al-Garawi A, Sole M, Colmenero J, Nicolas JM, Jimenez W, Weich N, Gutierrez-Ramos JC, Arroyo V, Rodes J: Activated human hepatic stellate cells express the renin-angiotensin system and synthesize angiotensin II. Gastroenterology 125:117–125, 2003PubMedGoogle Scholar
  8. 8.
    Loetscher P, Seitz M, Clark-Lewis I, Baggiolini M, Moser B: Monocyte chemotactic proteins MCP-1, MCP-2, and MCP-3 are major attractants for human CD4+ and CD8+ T lymphocytes. FASEB J 8:1055–1060, 1994PubMedGoogle Scholar
  9. 9.
    Gressner AM: Cytokines and cellular crosstalk involved in the activation of fat-storing cells. J Hepatol 22:28–36, 1995PubMedGoogle Scholar
  10. 10.
    Bernuau D, Rogier E, Feldmann G: In situ ultrastructural detection and quantitation of liver mononuclear phagocytes in contact with hepatocytes in chronic type B hepatitis. Lab Invest 51:667–674, 1984PubMedGoogle Scholar
  11. 11.
    Narumi S, Tominaga Y, Tamaru M, Shimai S, Okumura H, Nishioji K, Itoh Y, Okanoue T: Expression of IFN-inducible protein-10 in chronic hepatitis. J Immunol 158:5536–5544, 1997PubMedGoogle Scholar
  12. 12.
    Marra F, DeFranco R, Grappone C, Milani S, Pastacaldi S, Pinzani M, Romanelli RG, Laffi G, Gentilini P: Increased expression of monocyte chemotactic protein-1 during active hepatic fibrogenesis: correlation with monocyte infiltration. Am J Pathol 152:423–430, 1998PubMedGoogle Scholar
  13. 13.
    Funakoshi Y, Ichiki T, Shimokawa H, Egashira K, Takeda K, Kaibuchi K, Takeya M, Yoshimura T, Takeshita A: Rho-kinase mediates angiotensin II-induced monocyte chemoattractant protein-1 expression in rat vascular smooth muscle cells. Hypertension 38:100–104, 2001PubMedGoogle Scholar
  14. 14.
    Omura T, Yoshiyama M, Kim S, Matsumoto R, Nakamura Y, Izumi Y, Ichijo H, Sudo T, Akioka K, Iwao H, Takeuchi K, Yoshikawa J: Involvement of apoptosis signal-regulating kinase-1 on angiotensin II-induced monocyte chemoattractant protein-1 expression. Arterioscler Thromb Vasc Biol 24:270–275, 2004CrossRefPubMedGoogle Scholar
  15. 15.
    Yee HF Jr: Rho directs activation-associated changes in rat hepatic stellate cell morphology via regulation of the actin cytoskeleton. Hepatology 28:843–850, 1998CrossRefPubMedGoogle Scholar
  16. 16.
    Kato M, Iwamoto H, Higashi N, Sugimoto R, Uchimura K, Tada S, Sakai H, Nakamuta M, Nawata H: Role of Rho small GTP binding protein in the regulation of actin cytoskeleton in hepatic stellate cells. J Hepatol 31:91–99, 1999CrossRefPubMedGoogle Scholar
  17. 17.
    Tada S, Iwamoto H, Nakamuta M, Sugimoto R, Enjoji M, Nakashima Y, Nawata H: A selective ROCK inhibitor, Y27632, prevents dimethylnitrosamine-induced hepatic fibrosis in rats. J Hepatol 34:529–536, 2001CrossRefPubMedGoogle Scholar
  18. 18.
    Murata T, Arii S, Nakamura T, Mori A, Kaido T, Furuyama H, Furumoto K, Nakao T, Isobe N, Imamura M: Inhibitory effect of Y-27632, a ROCK inhibitor, on progression of rat liver fibrosis in association with inactivation of hepatic stellate cells. J Hepatol 35:474–481, 2001CrossRefPubMedGoogle Scholar
  19. 19.
    Sugaya T, Nishimatsu S, Tanimoto K, Takimoto E, Yamagishi T, Imamura K, Goto S, Imaizumi K, Hisada Y, Otsuka A, Uchida H, Sugiura K, Fukuta K, Fukamizu A, Murakami K: Angiotensin II type 1a receptor-deficient mice with hypotension and hyperreninemia, J Biol Chem 270:18719–18722, 1995CrossRefPubMedGoogle Scholar
  20. 20.
    Murakami K, Abe T, Miyazawa M, Yamaguchi M, Masuda T, Matsuura T, Nagamori S, Takeuchi K, Abe K, Kyogoku M: Establishment of a new human cell line, LI90, exhibiting characteristics of hepatic Ito (fat-storing) cells. Lab Invest 72:731–739, 1995PubMedGoogle Scholar
  21. 21.
    Ousman SS, David S: MIP-1 alpha, MCP-1, GM-CSF, and TNF-alpha control the immune cell response that mediates rapid phagocytosis of myelin from the adult mouse spinal cord. J Neurosci 21:4649–4656, 2001PubMedGoogle Scholar
  22. 22.
    Von Bubnoff D, Matz H, Cazenave JP, Hanau D, Bieber T, De La Salle H: Kinetics of gene induction after Fc epsilon RI ligation of atopic monocytes identified by suppression subtractive hybridization. J Immunol 169:6170–6177, 2002PubMedGoogle Scholar
  23. 23.
    Kamai T, Arai K, Tsujii T, Honda M, Yoshida K: Overexpression of RhoA mRNA is associated with advanced stage in testicular germ cell tumour. BJU Int 87:227–231, 2001CrossRefPubMedGoogle Scholar
  24. 24.
    Terui Y, Saito T, Watanabe H, Togashi H, Kawata S, Kamada Y, Sakuta S: Effect of angiotensin receptor antagonist on liver fibrosis in early stages of chronic hepatitis C. Hepatology 36:1022, 2002CrossRefPubMedGoogle Scholar
  25. 25.
    Bataller R, Gabele E, Schoonhoven R, Morris T, Lehnert M, Yang L, Brenner DA, Rippe RA: Prolonged infusion of angiotensin II into normal rats induces stellate cell activation and proinflammatory events in liver. Am J Physiol Gastrointest Liver Physiol 285:G642–G651, 2003PubMedGoogle Scholar
  26. 26.
    Czaja MJ, Geerts A, Xu J, Schmiedeberg P, Ju Y: Monocyte chemo- attractant protein 1 (MCP-1) expression occurs in toxic rat liver injury and human liver disease. J Leukoc Biol 55:120–126, 1994PubMedGoogle Scholar
  27. 27.
    Afford SC, Fisher NC, Neil DA, Fear J, Brun P, Hubscher SG, Adams DH: Distinct patterns of chemokine expression are associated with leukocyte recruitment in alcoholic hepatitis and alcoholic cirrhosis. J Pathol 186:82–89, 1998CrossRefPubMedGoogle Scholar
  28. 28.
    Luckey SW, Petersen DR: Activation of Kupffer cells during the course of carbon tetrachloride-induced liver injury and fibrosis in rats. Exp Mol Pathol 71:226–240, 2001CrossRefPubMedGoogle Scholar
  29. 29.
    Phillips MI, Kagiyama S: Angiotensin II as a pro-inflammatory mediator. Curr Opin Investig Drugs 3:569–577, 2002PubMedGoogle Scholar
  30. 30.
    Pinzani M, Marra F: Cytokine receptors and signaling in hepatic stellate cells. Semin Liver Dis 21:397–416, 2001CrossRefPubMedGoogle Scholar
  31. 31.
    Kunieda Y, Nakagawa K, Nishimura H, Kato H, Ukimura N, Yano S, Kawano H, Kimura S, Nakagawa M, Tsuji H: HMG CoA reductase inhibitor suppresses the expression of tissue factor and plasminogen activator inhibitor-1 induced by angiotensin II in cultured rat aortic endothelial cells. Thromb Res 110:227–234, 2003CrossRefPubMedGoogle Scholar
  32. 32.
    Ueda A, Okuda K, Ohno S, Shirai A, Igarashi T, Matsunaga K, Fukushima J, Kawamoto S, Ishigatsubo Y, Okubo T: NF-kappa B and Sp1 regulate transcription of the human monocyte chemoattractant protein-1 gene. J Immunol 153:2052–2063, 1994PubMedGoogle Scholar
  33. 33.
    Hernandez-Presa M, Bustos C, Ortego M, Tunon J, Renedo G, Ruiz-Ortega M, Egido J: Angiotensin-converting enzyme inhibition prevents arterial nuclear factor-kappa B activation, monocyte chemoattractant protein-1 expression, and macrophage infiltration in a rabbit model of early accelerated atherosclerosis. Circulation 95:1532–1541, 1997PubMedGoogle Scholar
  34. 34.
    Ruiz-Ortega M, Bustos C, Hernandez-Presa MA, Lorenzo O, Plaza JJ, Egido J: Angiotensin II participates in mononuclear cell recruitment in experimental immune complex nephritis through nuclear factor-kappa B activation and monocyte chemoattractant protein-1 synthesis. J Immunol 161:430–439, 1998PubMedGoogle Scholar
  35. 35.
    Bataller R, Schwabe RF, Choi YH, Yang L, Paik YH, Lindquist J, Qian T, Schoonhoven R, Hagedorn CH, Lemasters JJ, Brenner DA: NADPH oxidase signal transduces angiotensin II in hepatic stellate cells and is critical in hepatic fibrosis. J Clin Invest 112:1383–1394, 2003CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science + Business Media, Inc. 2005

Authors and Affiliations

  • Keishi Kanno
    • 1
  • Susumu Tazuma
    • 2
    • 3
    Email author
  • Tomoji Nishioka
    • 1
  • Hideyuki Hyogo
    • 2
  • Kazuaki Chayama
    • 1
  1. 1.Department of Medicine and Molecular Science, Graduate School of Biomedical SciencesHiroshima UniversityHiroshimaJapan
  2. 2.Division of General MedicineHiroshima University Medical HospitalHiroshimaJapan
  3. 3.Division of General MedicineHiroshima University Medical HospitalHiroshimaJapan

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