Skip to main content
SpringerLink
Log in

Effect of Losartan, an Angiotensin II Antagonist, on Hepatic Fibrosis Induced by CCl4 in Rats

  • Published:
Digestive Diseases and Sciences Aims and scope Submit manuscript

Abstract

In addition to regulating blood pressure and body fluid homeostasis, the renin-angiotensin system (RAS) is also involved in hepatic fibrogenesis. We aimed to investigate the effect of losartan, an angiotensin II (Ang II) antagonist, on CCl4-induced hepatic fibrosis in rats. Hepatic fibrosis was induced by a subcutaneous injection with 50% CCl4 in Sprague-Dawley rats. The amount of CCl4 administered was 1 mg/kg. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in plasma and hydroxyproline (Hyp) contents in liver tissue were assayed by spectrophotometry. Hyaluronic acid (HA) and procollagen III (PC III) were assessed by radioimmunoassay. Tumor necrosis factor-α (TNF-α) and transforming growth factor-β 1 (TGF-β 1) levels in culture supernatants of Kupffer cells (KCs) stimulated with Ang II was determined by ELISA. Liver samples collected after 12 weeks of CCl4 treatment were stained with hematoxylin and eosin, then scored. Losartan (2.5, 5, and 10 mg·kg−1, ig) and captopril (100 mg·kg−1, ig) significantly decreased liver and spleen indexes, serum transaminase (AST, ALT) activities, HA and PC III levels, and Hyp contents in liver tissue in rats of hepatic fibrosis. Histopathological scores showed that losartan had an inhibitory effect on the progression of hepatic fibrosis. In in vitro experiments, losartan (1 × 10−9-1 × 10−5 M) significantly reduced TNF-α and TGF-β1 levels in culture supernatants of KCs, but captopril (1× 10−5 M) did not. The results showed that losartan significantly inhibited the progression of hepatic fibrosis induced by CCl4, and the inhibitory effect of losartan on hepatic fibrosis might be associated with its ability to inhibit the production of TNF-α and TGF-β 1 by activated KCs.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

REFERENCES

  1. Beljaars L, Meijer DK, Poelstra K: Targeting hepatic stellate cells for cell-specific treatment of liver fibrosis. Front Biosci 7:214-222, 2002

    Google Scholar 

  2. Toda K, Kumagai N, Tsuchimoto K, Inagaki H, Suzuki T, Oishi T, Atsukawa K, Saito H, Morizane T, Hibi T, Ishii H: Induction of hepatic stellate cell proliferation by LPS-stimulated peripheral blood mononuclear cells from patients with liver cirrhosis. J Gastroenterol 35:214-220, 2000

    Article  PubMed  Google Scholar 

  3. Friedman SL: Parenchymal Fe and collagen gene expression: An iron-clad association? Hepatology 21:1197-1199, 1995

    Article  PubMed  Google Scholar 

  4. Zhang X, Yu WP, Gao L, Wei KB, Ju JL, Xu JZ: Effects of lipopolysaccharides stimulated Kupffer cells on activation of rat hepatic stellate cells. World J Gastroenterol 10:610-613, 2004

    PubMed  Google Scholar 

  5. Helmy A, Jalan R, Newby DE, Hayes PC, Webb DJ: Role of angiotensin II in regulation of basal and sympathetically stimulated vascular tone in early and advanced cirrhosis. Gastroenterology 118:565-572, 2000

    PubMed  Google Scholar 

  6. Rockey DC, Weisiger RA: Endothelin induced contractility of stellate cells from normal and cirrhotic rat liver: Implications for regulation of portal pressure and resistance. Hepatology 24:233-240, 1996

    Article  PubMed  Google Scholar 

  7. 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, 2001

    Article  PubMed  Google Scholar 

  8. 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, 2001

    PubMed  Google Scholar 

  9. 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, 2000

    PubMed  Google Scholar 

  10. Leung PS, Suen PM, Ip SP, Yip CK, Chen G, Lai PB: Expression and localization of AT1 receptors in hepatic Kupffer cells: Its potential role in regulating a fibrogenic response. Regul Pept 116:61-69, 2003

    Article  PubMed  Google Scholar 

  11. Casini A: Alcohol-induced fatty liver and inflammation: Where do Kupffer cells act? J Hepatol 32:1026-1030, 2000

    Article  PubMed  Google Scholar 

  12. Zhang JP, Zhang M, Zhou JP, Liu FT, Zhou B, Xie WF, Guo C: Antifibrotic effects of matrine on in vitro and in vivo models of liver fibrosis in rats. Acta Pharmacol Sin 22:183-186, 2001

    PubMed  Google Scholar 

  13. Smedsrod B, Pertoft H, Eggertsen G, Sundstrom C: Functional and morphological characterization of cultures of Kupffer cells and liver endothelial cells prepared by means of density separation in Percoll, and selective substrate adherence. Cell Tissue Res 241:639-649, 1985

    PubMed  Google Scholar 

  14. Mitchell AD, Taylor IE: The spectrophotometric determination of hydroxyproline:Ananalytical investigation. Analyst 95:1003-1011, 1970

    Article  PubMed  Google Scholar 

  15. Hernandez-Munoz R, Diaz-Munoz M, Lopez V, Lopez-Barrera F, Yanez L, Vidrio S, Aranda-Fraustro A, Chagoya de Sanchez V: Balance between oxidative damage and proliferative potential in an experimental rat model of CCl4-induced cirrhosis: Protective role of adenosine administration. Hepatology 26:1100-1110, 1997

    PubMed  Google Scholar 

  16. 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(4). World J Gastroenterol 6:540-545, 2000

    PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  18. Croquet V, Moal F, Veal N, Wang J, Oberti F, Roux J, Vuillemin E, Gallois Y, Douay O, Chappard D, Cales P: Hemodynamic and antifibrotic effects of losartan in rats with liver fibrosis and/or portal hypertension. J Hepatol 37:773-780, 2002

    Article  PubMed  Google Scholar 

  19. Tada S, Nakamuta M, Enjoji M, Sugimoto R, Iwamoto H, Kato M, Nakashima Y, Nawata H: Pirfenidone inhibits dimethylnitrosamineinduced hepatic fibrosis in rats. Clin Exp Pharmacol Physiol 28:522-527, 2001

    Article  PubMed  Google Scholar 

  20. Ramalho LN, Ramalho FS, Zucoloto S, Castro-e-Silva Junior O, Correa FM, Elias Junior J, Magalhaes JF: Effect of losartan, an angiotensin II antagonist, on secondary biliary cirrhosis. Hepatogastroenterology 49:1499-1502, 2002

    PubMed  Google Scholar 

  21. Shi J, Aisaki K, Ikawa Y, Wake K: Evidence of hepatocyte apoptosis in rat liver after the administration of carbon tetrachloride. Am J Pathol 153:515-525, 1998

    PubMed  Google Scholar 

  22. Thompson K, Maltby J, Fallowfield J, McAulay M, Millward-Sadler H, Sheron N: Interleukin-10 expression and function in experimental murine liver inflammation and fibrosis. Hepatology 28:1597-1606, 1998

    Article  PubMed  Google Scholar 

  23. Simeonova PP, Gallucci RM, Hulderman T, Wilson R, Kommineni C, Rao M, Luster Ml: The role of tumor necrosis factor-alpha in liver toxicity, inflammation, and fibrosis induced by carbon tetrachloride. Toxicol Appl Pharmacol 177:112-120, 2001

    Article  PubMed  Google Scholar 

  24. 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, 2001

    Article  PubMed  Google Scholar 

  25. Sugata K, Kamimura S, Shijo H: Differential effects between tauroursodeoxycholic and taurochenodeoxycholic acids in hepatic fibrosis: An assessment by primary cultured Ito and Kupffer cells from the rat liver. J Gastroenterol Hepatol 11:451-458, 1996

    PubMed  Google Scholar 

  26. Wu J, Zern MA: Hepatic stellate cells: A target for the treatment of liver fibrosis. J Gastroenterol 35:665-672, 2000

    Article  PubMed  Google Scholar 

  27. De Bleser PJ, Niki T, Rogiers V, Geerts A: Transforming growth factor-beta gene expression in normal and fibrotic rat liver. J Hepatol 26:886-893, 1997

    Article  PubMed  Google Scholar 

  28. George J, Roulot D, Koteliansky VE, Bissell DM: In vivo inhibition of rat stellate cell activation by soluble transforming growth factor beta type II receptor: A potential new therapy for hepatic fibrosis. Proc Natl Acad Sci USA 96:12719-12724, 1999

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou, 310031

    Yao Hong Wei & Chen Ji Qiang

  2. Institute of Clinical Pharmacology, Anhui Medical University, Hefei, 230032, China

    Li Jun

Authors
  1. Yao Hong Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Li Jun
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chen Ji Qiang
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wei, Y.H., Jun, L. & Qiang, C.J. Effect of Losartan, an Angiotensin II Antagonist, on Hepatic Fibrosis Induced by CCl4 in Rats. Dig Dis Sci 49, 1589–1594 (2004). https://doi.org/10.1023/B:DDAS.0000043369.88701.5b

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/B:DDAS.0000043369.88701.5b

Search

Navigation