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Effect of Angiotensin-converting Enzyme Inhibition on Experimental Hepatic Fibrogenesis

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Abstract

The renin-angiotensin system is suggested to be important in liver fibrogenesis. It induces hepatic stellate cell proliferation and up-regulates transforming growth factor beta-1 (TGF-β1) expression. Matrix metalloproteinase-2 (MMP-2) is involved in extracellular matrix remodelling. Fibrosis, a consequence of most chronic liver diseases, may be the result of a disturbed balance between fibrogenesis and fibrolysis. The aim of this study was to investigate the effect of enalapril on liver fibrogenesis induced in rats by bile-duct ligation. Forty-seven rats were divided into two groups: bile-duct ligated (BDL) (n = 24) and BDL + enalapril (n = 23). Fibrosis was evaluated by the Knodell scoring system, and TGF-β1 and MMP-2 were assessed with immunohistochemistry at the second, fourth and sixth weeks after bile-duct ligation. In the BDL group, TGF-β1 increased by the second week and this increase continued through weeks 4 and 6. In the BDL + enalapril group, TGF-β1 was significantly lower than the other group (P < 0.05). MMP-2 progressively decreased after week 2 in the BDL group. In the BDL + enalapril group, MMP-2 was significantly higher than the BDL group at the fourth and sixth weeks. These results suggest that enalapril reduces the liver tissue TGF-β1 and has an ameliorating effect on the fibrosis markers TGF-β1 and MMP-2.

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References

  1. Wright MC, Issa R, Smart DE, Trim N, Murray GI, Primrose JN, Arthur MJ, Iredale JP, Mann DA (2001) Glitoxin stimulates the apoptosis of human and rat hepatic stellate cells and enhances the resolution of liver fibrosis in rats. Gastroenterology 121:685–698

    Article  PubMed  CAS  Google Scholar 

  2. Knittel T, Kobold D, Saile B, Grundmann A, Neubauer K, Piscaglia F, Ramadori G (1999) Rat liver myofibroblasts and hepatic stellate cells: different cell populations of the fibroblast lineage with fibrogenic potential. Gastroenterology 117:1205–1221

    Article  PubMed  CAS  Google Scholar 

  3. Kawada N (2004) Molecular mechanism of stellate activation and therapeutic strategy for liver fibrosis. Comp Hepatol 3(Suppl 1):S3

    Article  PubMed  Google Scholar 

  4. Bataller R, Gines P, Nicolas JM, Gorbig MN, Garcia-Ramallo E, Gasull X, Bosch J, Arroyo V, Rodes J (2000) Angiotensin II induces contraction and proliferation of human hepatic stellate cells. Gastroenterology 118:1149–1156

    Article  PubMed  CAS  Google Scholar 

  5. Yoshiji H, Kuriyama S, Yoshii J, Ikenaka Y, Noguchi R, Nakatani T, Tsujinoue H, Fukui H (2001) Angiotensin II type 1 receptor interaction is a major regulator for liver fibrosis development in rats. Hepatology 34:745–750

    PubMed  CAS  Google Scholar 

  6. Kim S, Ohta K, Hamaguchi A, Omura T, Yukimura T, Miura K, Inada Y, Ishimura Y, Chatani F, Iwao H (1995) Angiotensin II type 1 receptor antagonist inhibits the gene expression of transforming growth factor beta-1 and extracellular matrix in cardiac and vascular tissues of hypertensive rats. J Pharmacol Exp Ther 273:509–515

    PubMed  CAS  Google Scholar 

  7. Lee LK, Meyer TW, Pollock AS, Lovett DH (1995) Endothelial cell injury initiates glomerular sclerosis in the rat remnant kidney. J Clin Invest 96:953–964

    Article  PubMed  CAS  Google Scholar 

  8. Jonsson JR, Clouston AD, Ando Y, Kelemen LI, Horn MJ, Adamson MD, Purdie DM (2001) Angiotensin-converting enzyme inhibition attenuates the progression of rat hepatic fibrosis. Gastroenterology 121:148–155

    Article  PubMed  CAS  Google Scholar 

  9. Murawaki Y, Yamada S, Ikuta Y, Kawasaki H (1999) Clinical usefulness of serum matrix metalloproteinase-2 concentration in patients with chronic viral liver disease. J Hepatol 30:1090–1098

    Article  PubMed  CAS  Google Scholar 

  10. Watanabe T, Niioka M, Ishikawa A, Hozowa S, Arai M, Maruyama K, Okada A, Okazaki I (2001) Dynamic change of cells expressing MMP-2 mRNA and MT1-MMP mRNA in the recovery from liver fibrosis in the rat. J Hepatol 35:465–473

    Article  PubMed  CAS  Google Scholar 

  11. Weiner FR, Czaja MJ, Giambrone MA, Takahashi S, Biempica L, Zern MA (1987) Transcriptional and posttranscriptional effects of dexamethasone on albumin and procollagen messenger RNAs in murine schistosomiasis. Biochemistry 26:1557–1562

    Article  PubMed  CAS  Google Scholar 

  12. Czaja MJ, Weiner FR, Eghbali M, Giambrone MA, Eghbali M, Zern MA (1987) Differential effects of g-interferon on collagen and fibronectin gene expression. J Biol Chem 262:1348–1351

    Google Scholar 

  13. Kerchenobich D, Vargas F, Garcia-Tsao G, Perz Tamayo R, Gent M, Rojkind M (1988) Colchicine in the treatment of cirrhosis of the liver. N Engl J Med 318:1709–1713

    Article  Google Scholar 

  14. Wu LL, Cox A, Roe CJ, Dziadek M, Cooper ME, Gilbert RE (1997) Transforming growth factor beta 1 and renal injury following subtotal nephrectomy in the rat: role of the renin angiotensin system. Kidney Int 51:1553–1567

    Article  PubMed  CAS  Google Scholar 

  15. De Carvalho Frimm C, Sun Y, Weber KT (1997) Angiotensin II receptor blockade and myocardial fibrosis of the infarcted rat heart. J Lab Clin Med 129:439–446

    Article  PubMed  Google Scholar 

  16. Friedman SL (1999) The virtuosity of hepatic stellate cells. Gastroenterology 117:1244–1246

    Article  PubMed  CAS  Google Scholar 

  17. Ohishi T, Saito H, Tsusaka K, Toda K, Inagaki H, Hamada Y, Kumagai Y, Atsukawa K, Ishii H (2001) Anti-fibrogenic effect of an angiotensin converting enzyme inhibitor on chronic carbon tetrachloride-induced hepatic fibrosis in rats. Hepatol Res 21:147–158

    Article  PubMed  CAS  Google Scholar 

  18. Toblli JE, Ferder L, Stella I, Angerosa M, Inserra F (2002) Enalapril prevents fatty liver in nephrotic rats. J Nephrol 15:358–367

    PubMed  CAS  Google Scholar 

  19. Wei HS, Lu HM, Li DG, Zhan YT, Wang ZR, Huang X, Cheng JL, Xu OF (2000) The regulatory role of AT 1 receptor on activated HSCs in hepatic fibrogenesis: effects of RAS inhibitors on hepatic fibrosis induced by CCl4. World J Gastroenterol 6:824–828

    PubMed  CAS  Google Scholar 

  20. Paizis G, Gilbert RE, Cooper ME, Murthi P, Schembri JM, Wu LL, Rumble JR, Kelly DJ, Tikellis C, Cox A, Smallwood RA, Angus PW (2001) Effect of angiotensin II type 1 receptor blockade on experimental hepatic fibrogenesis. J Hepatol 35:376–385

    Article  PubMed  CAS  Google Scholar 

  21. Kurikawa N, Suga M, Kuroda S, Yamada K, Ishikawa H (2003) An angiotensin II type 1 receptor antagonist, olmesartan medoxamil improves experimental liver fibrosis by suppress of proliferation and collagen synthesis in activated hepatic stellate cells. Br J Pharmacol 139(6):1085–1094

    Article  PubMed  CAS  Google Scholar 

  22. Lichtinghagen R, Michels D, Haberkorn CI, Arndt B, Bahr M, Flemming P, Manns MP, Boeker KH (2001) Matrix metalloproteinase (MMP)-2, MMP-7, and tissue inhibitor of metalloproteinase-1 are closely related to the fibroproliferative process in the liver during chronic hepatitis C. J Hepatol 34:239–247

    Article  PubMed  CAS  Google Scholar 

  23. Lee H, Huang G (2001) Less reversal of liver fibrosis after prolonged carbon tetrachloride injection. Hepatogastroenterology 48:1312–1315

    PubMed  CAS  Google Scholar 

  24. Takahara T, Furui K, Funaki J, Nakayama Y, Itoh H, Miyabayashi C, Sato H, Seiki M, Ooshima A, Watanabe A (1995) Increased expression of matrix metalloproteinase II in experimental liver fibrosis in rats. Hepatology 21:787–794

    Article  PubMed  CAS  Google Scholar 

  25. Takahara T, Furui K, Yata Y, Jin B, Zhang LP, Nambu S, Sato H, Seiki M, Watanabe A (1997) Dual expression of matrix metalloproteinase II and membrane type-1 matrix metalloproteinase in fibrotic human livers. Hepatology 26:1521–1529

    Article  PubMed  CAS  Google Scholar 

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Correspondence to Mehmet Kanbay.

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Türkay, C., Yönem, Ö., Arıcı, S. et al. Effect of Angiotensin-converting Enzyme Inhibition on Experimental Hepatic Fibrogenesis. Dig Dis Sci 53, 789–793 (2008). https://doi.org/10.1007/s10620-007-9941-y

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  • DOI: https://doi.org/10.1007/s10620-007-9941-y

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