Abstract
Aim:
To evaluate the antifibrotic effect of telmisartan, an angiotensin II receptor blocker, in bile duct-ligated rats.
Methods:
Adult Sprague-Dawley rats were allocated to 3 groups: sham-operated rats, model rats underwent common bile duct ligation (BDL), and BDL rats treated with telmisartan (8 mg/kg, po, for 4 weeks). The animals were sacrificed on d 29, and liver histology was examined, the Knodell and Ishak scores were assigned, and the expression of angiotensin-converting enzyme (ACE) and ACE2 was evaluated with immunohistochemical staining. The mRNAs and proteins associated with liver fibrosis were evaluated using RTQ-PCR and Western blot, respectively.
Results:
The mean fibrosis score of BDL rats treated with telmisartan was significantly lower than that of the model rats (1.66±0.87 vs 2.13±0.35, P=0.015). However, there was no significant difference in inflammation between the two groups, both of which showed moderate inflammation. Histologically, treatment with telmisartan significantly ameliorated BDL-caused the hepatic fibrosis. Treatment with telmisartan significantly upregulated the mRNA levels of ACE2 and MAS, and decreased the mRNA levels of ACE, angiotensin II type 1 receptor (AT1-R), collagen type III, and transforming growth factor β1 (TGF-β1). Moreover, treatment with telmisartan significantly increased the expression levels of ACE2 and MAS proteins, and inhibited the expression levels of ACE and AT1-R protein.
Conclusion:
Telmisartan attenuates liver fibrosis in bile duct-ligated rats via increasing ACE2 expression level.
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References
Pereira RM, Dos Santos RA, Teixeira MM, Leite VH, Costa LP, da Costa Dias FL, et al. The renin-angiotensin system in a rat model of hepatic fibrosis: evidence for a protective role of angiotensin-(1–7). J Hepatol 2007; 46: 674–81.
Lubel JS, Herath CB, Burrell LM, Angus PW . Liver disease and the renin-angiotensin system: recent discoveries and clinical implications. J Gastroenterol Hepatol 2008; 23: 1327–38.
Paizis G, Tikellis C, Cooper ME, Schembri JM, Lew RA, Smith AI, et al. Chronic liver injury in rats and humans upregulates the novel enzyme angiotensin converting enzyme 2. Gut 2005; 54: 1790–6.
Castro-Chaves P, Cerqueira R, Pintalhao M, Leite-Moreira AF . New pathways of the renin-angiotensin system: the role of ACE2 in cardiovascular pathophysiology and therapy. Expert Opin Ther Targets 2010; 14: 485–96.
Dejima T, Tamura K, Wakui H, Maeda A, Ohsawa M, Kanaoka T, et al. Prepubertal angiotensin blockade exerts long-term therapeutic effect through sustained ATRAP activation in salt-sensitive hypertensive rats. J Hypertens 2011; 29: 1919–29.
Huang ML, Li X, Meng Y, Xiao B, Ma Q, Ying SS, et al. Upregulation of angiotensin-converting enzyme (ACE) 2 in hepatic fibrosis by ACE inhibitors. Clin Exp Pharmacol Physiol 2010; 37: e1–6.
Lubel JS, Herath CB, Tchongue J, Grace J, Jia Z, Spencer K, et al. Angiotensin-(1–7), an alternative metabolite of the renin-angiotensin system, is up-regulated in human liver disease and has antifibrotic activity in the bile-duct-ligated rat. Clin Sci (Lond) 2009; 117: 375–86.
Moreno M, Gonzalo T, Kok RJ, Sancho-Bru P, van Beuge M, Swart J, et al. Reduction of advanced liver fibrosis by short-term targeted delivery of an angiotensin receptor blocker to hepatic stellate cells in rats. Hepatology 2010; 51: 942–52.
Corey KE, Shah N, Misdraji J, Abu Dayyeh BK, Zheng H, Bhan AK, et al. The effect of angiotensin-blocking agents on liver fibrosis in patients with hepatitis C. Liver Int 2009; 29: 748–53.
Soler MJ, Ye M, Wysocki J, William J, Lloveras J, Batlle D . Localization of ACE2 in the renal vasculature: amplification by angiotensin II type 1 receptor blockade using telmisartan. Am J Physiol Renal Physiol 2009; 296: F398–405.
Yang L, Bataller R, Dulyx J, Coffman TM, Gines P, Rippe RA, et al. Attenuated hepatic inflammation and fibrosis in angiotensin type 1a receptor deficient mice. J Hepatol 2005; 43: 317–23.
Bataller R, Gabele E, Parsons CJ, Morris T, Yang L, Schoonhoven R, et al. Systemic infusion of angiotensin II exacerbates liver fibrosis in bile duct-ligated rats. Hepatology 2005; 41: 1046–55.
Schuppan D, Gorrell MD, Klein T, Mark M, Afdhal NH . The challenge of developing novel pharmacological therapies for non-alcoholic steatohepatitis. Liver Int 2010; 30: 795–808.
Iwai M, Horiuchi M . Devil and angel in the renin-angiotensin system: ACE-angiotensin II-AT1 receptor axis vs ACE2-angiotensin-(1–7)-Mas receptor axis. Hypertens Res 2009; 32: 533–6.
Tallant EA, Ferrario CM, Gallagher PE . Angiotensin-(1–7) inhibits growth of cardiac myocytes through activation of the mas receptor. Am J Physiol Heart Circ Physiol 2005; 289: H1560–6.
Li N, Zimpelmann J, Cheng K, Wilkins JA, Burns KD . The role of angiotensin converting enzyme 2 in the generation of angiotensin 1–7 by rat proximal tubules. Am J Physiol Renal Physiol 2005; 288: F353–62.
Knodell RG, Ishak KG, Black WC, Chen TS, Craig R, Kaplowitz N, et al. Formulation and application of a numerical scoring system for assessing histological activity in asymptomatic chronic active hepatitis. Hepatology 1981; 1: 431–5.
Moriyama T, Aoyama H, Ohnishi S, Imawari M . Protective effects of fibronectin in galactosamine-induced liver failure in rats. Hepatology 1986; 6: 1334–9.
Kim MY, Baik SK, Park DH, Jang YO, Suk KT, Yea CJ, et al. Angiotensin receptor blockers are superior to angiotensin-converting enzyme inhibitors in the suppression of hepatic fibrosis in a bile duct-ligated rat model. J Gastroenterol 2008; 43: 889–96.
Karimian G, Mohammadi-Karakani A, Sotoudeh M, Ghazi-Khansari M, Ghobadi G, Shakiba B . Attenuation of hepatic fibrosis through captopril and enalapril in the livers of bile duct ligated rats. Biomed Pharmacother 2008; 62: 312–6.
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: 801–7.
Kaji K, Yoshiji H, Kitade M, Ikenaka Y, Noguchi R, Shirai Y, et al. Combination treatment of angiotensin II type I receptor blocker and new oral iron chelator attenuates progression of nonalcoholic steatohepatitis in rats. Am J Physiol Gastrointest Liver Physiol 2011; 300: G1094–104.
Sukumaran V, Veeraveedu PT, Gurusamy N, Yamaguchi K, Lakshmanan AP, Ma M, et al. Cardioprotective effects of telmisartan against heart failure in rats induced by experimental autoimmune myocarditis through the modulation of angiotensin-converting enzyme-2/angiotensin 1–7/mas receptor axis. Int J Biol Sci 2011; 7: 1077–92.
Dilauro M, Zimpelmann J, Robertson SJ, Genest D, Burns KD . Effect of ACE2 and angiotensin-(1–7) in a mouse model of early chronic kidney disease. Am J Physiol Renal Physiol 2010; 298: F1523–32.
Conner KR, Forbes ME, Lee WH, Lee YW, Riddle DR . AT1 receptor antagonism does not influence early radiation-induced changes in microglial activation or neurogenesis in the normal rat brain. Radiat Res 2011; 176: 71–83.
Herath CB, Warner FJ, Lubel JS, Dean RG, Jia Z, Lew RA, et al. Upregulation of hepatic angiotensin-converting enzyme 2 (ACE2) and angiotensin-(1–7) levels in experimental biliary fibrosis. J Hepatol 2007; 47: 387–95.
Acknowledgements
This study was supported by a grant from the National Natural Science Foundation of China (81073131/H2814).
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Yi, Et., Liu, Rx., Wen, Y. et al. Telmisartan attenuates hepatic fibrosis in bile duct-ligated rats. Acta Pharmacol Sin 33, 1518–1524 (2012). https://doi.org/10.1038/aps.2012.115
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DOI: https://doi.org/10.1038/aps.2012.115
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