Abstract
Background
Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease leading to cirrhosis and cholangiocellular carcinoma. Inhibitors of the renin–angiotensin system or the sympathetic nervous system delay liver fibrogenesis in animal models.
Aims
We investigated the antifibrotic potential of telmisartan, an angiotensin II type 1 receptor antagonist, and the β-adrenoceptor blocker propranolol in the PSC-like Abcb4 knockout mouse model.
Methods
Sixty-five Abcb4−/− mice were treated with telmisartan for 3 or 5 months (T) and with telmisartan plus propranolol for 3, 5, or 8 months (TP), or for 2 or 5 months starting with a delay of 3 months (TP delayed). Liver hydroxyproline content, inflammation, fibrosis, and bile duct proliferation were assessed; fibrosis-related molecules were analyzed by real-time polymerase chain reaction and Western blotting.
Results
Compared to controls, telmisartan monotherapy had no significant influence on hydroxyproline; however, telmisartan plus propranolol reduced hydroxyproline (TP 3 months, p = 0.008), fibrosis score (TP 3 months and TP 8 months, p = 0.043 and p = 0.008, respectively; TP delayed 8 months, p < 0.0005), bile duct proliferation (TP 8 months and TP delayed 8 months, p = 0.006 and p < 0.0005, respectively), and procollagen α1(I), endothelin-1, TIMP-1 and MMP3 mRNA as well as α-SMA, CK-19, and TIMP-1 protein.
Conclusions
Telmisartan plus propranolol reduces liver fibrosis and bile duct proliferation in the PSC-like Abcb4−/− mouse model, even when started at late stages of fibrosis, and may thus represent a novel therapeutic option for cholestatic liver diseases such as PSC.
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Abbreviations
- α-SMA:
-
α-Smooth muscle actin
- ADR:
-
Adrenoceptor
- Ang II:
-
Angiotensin II
- ACE:
-
Angiotensin converting enzyme
- AT1R:
-
Angiotensin II type 1 receptor
- ARB:
-
Angiotensin II type 1 receptor blocker
- CTGF:
-
Connective tissue growth factor
- CK-19:
-
Cytokeratin-19
- ET-1:
-
Endothelin-1
- ECM:
-
Extracellular matrix
- HSC:
-
Hepatic stellate cell
- MMP:
-
Matrix metalloproteinase
- PSC:
-
Primary sclerosing cholangitis
- PC-α1:
-
Procollagen α1(I)
- RT-PCR:
-
Real-time quantitative reverse transcription polymerase chain reaction
- RAS:
-
Renin–angiotensin system
- SNS:
-
Sympathetic nervous system
- TIMP:
-
Tissue inhibitor of matrix metalloproteinase
References
Weismüller T, Wedemeyer J, Kubicka S, Strassburg C, Manns M. The challenges in primary sclerosing cholangitis—aetiopathogenesis, autoimmunity, management and malignancy. J Hepatol. 2008;48:S38–S57.
Lindor K, Kowdley K, Luketic V, et al. High-dose ursodeoxycholic acid for the treatment of primary sclerosing cholangitis. Hepatology. 2009;50:808–814.
Ramadori G, Veit T, Schwogler S, et al. Expression of the gene of the alpha-smooth muscle-actin isoform in rat liver and in rat fat-storing (ITO) cells. Virchows Arch B Cell Pathol Incl Mol Pathol. 1990;59:349–357.
Wynn T. Cellular and molecular mechanisms of fibrosis. J Pathol. 2008;214:199–210.
Fickert P, Fuchsbichler A, Wagner M, et al. Regurgitation of bile acids from leaky bile ducts causes sclerosing cholangitis in Mdr2 (Abcb4) knockout mice. Gastroenterology. 2004;127:261–274.
Kawai M, Hongo K, Komukai K, et al. Telmisartan predominantly suppresses cardiac fibrosis, rather than hypertrophy, in renovascular hypertensive rats. Hypertens Res. 2009;32:604–610.
Naito T, Ma L, Yang H, et al. Angiotensin type 2 receptor actions contribute to angiotensin type 1 receptor blocker effects on kidney fibrosis. Am J Physiol Renal Physiol. 2009;298:F683–F691.
Töx U, Steffen HM. Impact of inhibitors of the renin–angiotensin–aldosterone system on liver fibrosis and portal hypertension. Curr Med Chem. 2006;13:3649–3661.
Bataller R, Ginès P, Nicolás J, et al. Angiotensin II induces contraction and proliferation of human hepatic stellate cells. Gastroenterology. 2000;118:1149–1156.
Barki-Harrington L, Luttrell L, Rockman H. Dual inhibition of beta-adrenergic and angiotensin II receptors by a single antagonist: a functional role for receptor–receptor interaction in vivo. Circulation. 2003;108:1611–1618.
Bataller R, Schwabe R, Choi Y, et al. NADPH oxidase signal transduces angiotensin II in hepatic stellate cells and is critical in hepatic fibrosis. J Clin Invest. 2003;112:1383–1394.
Goebel M, Clemenz M, Unger T. Effective treatment of hypertension by AT(1) receptor antagonism: the past and future of telmisartan. Expert Rev Cardiovasc Ther. 2006;4:615–629.
Kurtz TW, Pravenec M. Antidiabetic mechanisms of angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists: beyond the renin-angiotensin system. J Hypertens. 2004;22:2253–2261.
Nakagami H, Kiomy Osako M, Nakagami F, et al. Prevention and regression of non-alcoholic steatohepatitis (NASH) in a rat model by metabosartan, telmisartan. Int J Mol Med. 2010;26:477–481.
Okunuki Y, Usui Y, Nagai N, et al. Suppression of experimental autoimmune uveitis by angiotensin II type 1 receptor blocker telmisartan. Invest Ophthalmol Vis Sci. 2009;50:2255–2261.
Wang Z, Xu JP, Zheng YC, et al. Peroxisome proliferator-activated receptor gamma inhibits hepatic fibrosis in rats. Hepatobiliary Pancreat Dis Int. 2011;10:64–71.
Yang L, Stimpson SA, Chen L, Wallace Harrington W, Rockey DC. Effectiveness of the PPARgamma agonist, GW570, in liver fibrosis. Inflamm Res. 2010;59:1061–1071.
Oben J, Roskams T, Yang S, et al. Hepatic fibrogenesis requires sympathetic neurotransmitters. Gut. 2004;53:438–445.
Atlas S. The renin–angiotensin aldosterone system: pathophysiological role and pharmacologic inhibition. J Manag Care Pharm. 2007;13:9–20.
Oben J, Roskams T, Yang S, et al. Norepinephrine induces hepatic fibrogenesis in leptin deficient ob/ob mice. Biochem Biophys Res Commun. 2003;308:284–292.
Dubuisson L, Desmoulière A, Decourt B, et al. Inhibition of rat liver fibrogenesis through noradrenergic antagonism. Hepatology. 2002;35:325–331.
Oben J, Roskams T, Yang S, et al. Sympathetic nervous system inhibition increases hepatic progenitors and reduces liver injury. Hepatology. 2003;38:664–673.
Strack I, Schulte S, Varnholt H, et al. β-Adrenoceptor blockade in sclerosing cholangitis of Mdr2 knockout mice: antifibrotic effects in a model of nonsinusoidal fibrosis. Lab Invest. 2011;91:252–261.
Takaya T, Kawashima S, Shinohara M, et al. Angiotensin II type 1 receptor blocker telmisartan suppresses superoxide production and reduces atherosclerotic lesion formation in apolipoprotein E-deficient mice. Atherosclerosis. 2006;186:402–410.
Su J, Chen S, Wu K, et al. Effects of perindopril, propranolol, and dihydrochlorothiazide on cardiovascular remodelling in spontaneously hypertensive rats. Zhongguo Yao Li Xue Bao. 1999;20:923–928.
Schulte S, Oidtmann A, Kociok N, et al. Hepatocyte expression of angiotensin II type 1 receptor is downregulated in advanced human liver fibrosis. Liver Int. 2009;29:384–391.
Stegemann H, Stalder K. Determination of hydroxyproline. Clin Chim Acta. 1967;18:267–273.
Batts K, Ludwig J. Chronic hepatitis. An update on terminology and reporting. Am J Surg Pathol. 1995;19:1409–1417.
Chevallier M, Guerret S, Chossegros P, Gerard F, Grimaud J. A histological semiquantitative scoring system for evaluation of hepatic fibrosis in needle liver biopsy specimens: comparison with morphometric studies. Hepatology. 1994;20:349–355.
Farazi P, Zeisberg M, Glickman J, Zhang Y, Kalluri R, DePinho R. Chronic bile duct injury associated with fibrotic matrix microenvironment provokes cholangiocarcinoma in p53-deficient mice. Cancer Res. 2006;66:6622–6627.
Multi-system analysis of physiology on 7 inbred strains of mice. (Database on the Internet) 2011. Cited 20 Jan 2011. Available from: http://phenome.jax.org.
Silveira M, Lindor K. Primary sclerosing cholangitis. Can J Gastroenterol. 2008;22:689–698.
Kanno K, Tazuma S, Chayama K. AT1A-deficient mice show less severe progression of liver fibrosis induced by CCl(4). Biochem Biophys Res Commun. 2003;308:177–183.
Priester S, Wise C, Glaser SS. Involvement of cholangiocyte proliferation in biliary fibrosis. World J Gastroint Pathophysiol. 2010;1:30–37.
Trauner M, Fickert P, Baghdasaryan A, et al. New insights into autoimmune cholangitis through animal models. Dig Dis. 2010;28:99–104.
Pinzani M, Milani S, De Franco R, et al. Endothelin 1 is overexpressed in human cirrhotic liver and exerts multiple effects on activated hepatic stellate cells. Gastroenterology. 1996;110:534–548.
Rockey D, Chung J. Endothelin antagonism in experimental hepatic fibrosis. Implications for endothelin in the pathogenesis of wound healing. J Clin Invest. 1996;98:1381–1388.
He S, Prasanna G, Yorio T. Endothelin-1-mediated signaling in the expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases in astrocytes. Invest Ophthalmol Vis Sci. 2007;48:3737–3745.
Teerlink J. Reversal of left ventricular remodeling: role of the endothelin pathway. J Card Fail. 2002;8:S494–S499.
Schmitt-Gräff A, Chakroun G, Gabbiani G. Modulation of perisinusoidal cell cytoskeletal features during experimental hepatic fibrosis. Virchows Arch A Pathol Anat Histopathol. 1993;422:99–107.
Popov Y, Patsenker E, Fickert P, Trauner M, Schuppan D. Mdr2 (Abcb4)−/− mice spontaneously develop severe biliary fibrosis via massive dysregulation of pro- and antifibrogenic genes. J Hepatol. 2005;43:1045–1054.
Roderfeld M, Rath T, Voswinckel R, et al. Bone marrow transplantation demonstrates medullar origin of CD34+ fibrocytes and ameliorates hepatic fibrosis in Abcb4−/− mice. Hepatology. 2010;51:267–276.
Mayoral P, Criado M, Hidalgo F, et al. Effects of chronic nitric oxide activation or inhibition on early hepatic fibrosis in rats with bile duct ligation. Clin Sci (Lond). 1999;96:297–305.
Gomes A, Bastos C, Afonso C, Medrado B, Andrade Z. How variable are hydroxyproline determinations made in different samples of the same liver? Clin Biochem. 2006;39:1160–1163.
Iredale J, Benyon R, Arthur M, et al. Tissue inhibitor of metalloproteinase-1 messenger RNA expression is enhanced relative to interstitial collagenase messenger RNA in experimental liver injury and fibrosis. Hepatology. 1996;24:176–184.
Okazaki I, Watanabe T, Hozawa S, Niioka M, Arai M, Maruyama K. Reversibility of hepatic fibrosis: from the first report of collagenase in the liver to the possibility of gene therapy for recovery. Keio J Med. 2001;50:58–65.
Steenport M, Khan K, Du B, Barnhard S, Dannenberg A, Falcone D. Matrix metalloproteinase (MMP)-1 and MMP-3 induce macrophage MMP-9: evidence for the role of TNF-alpha and cyclooxygenase-2. J Immunol. 2009;183:8119–8127.
Border W, Noble N. Transforming growth factor beta in tissue fibrosis. N Engl J Med. 1994;331:1286–1292.
Nakken K, Nygård S, Haaland T, et al. Multiple inflammatory-, tissue remodelling- and fibrosis genes are differentially transcribed in the livers of Abcb4 (−/−) mice harbouring chronic cholangitis. Scand J Gastroenterol. 2007;42:1245–1255.
Jin H, Yamamoto N, Uchida K, Terai S, Sakaida I. Telmisartan prevents hepatic fibrosis and enzyme-altered lesions in liver cirrhosis rat induced by a choline-deficient l-amino acid-defined diet. Biochem Biophys Res Commun. 2007;364:801–807.
Acknowledgments
We greatly appreciate the excellent technical assistance of Gudrun Suckau and Brigitta Jacob. We are also indebted to Boehringer Ingelheim GmbH & Co. KG for kindly providing telmisartan. This work was supported by a grant from the Marga and Walter Boll Stiftung.
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Susanne Mende, Sigrid Schulte and Ingo Strack contributed equally to this work.
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Mende, S., Schulte, S., Strack, I. et al. Telmisartan Plus Propranolol Improves Liver Fibrosis and Bile Duct Proliferation in the PSC-Like Abcb4−/− Mouse Model. Dig Dis Sci 58, 1271–1281 (2013). https://doi.org/10.1007/s10620-012-2499-3
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DOI: https://doi.org/10.1007/s10620-012-2499-3