Browse > Article
http://dx.doi.org/10.3904/kjim.2017.317

Role of the renin-angiotensin system in hepatic fibrosis and portal hypertension  

Shim, Kwang Yong (Department of Internal Medicine, Yonsei University Wonju College of Medicine)
Eom, Young Woo (Cell Therapy and Tissue Engineering Center, Yonsei University Wonju College of Medicine)
Kim, Moon Young (Department of Internal Medicine, Yonsei University Wonju College of Medicine)
Kang, Seong Hee (Department of Internal Medicine, Yonsei University Wonju College of Medicine)
Baik, Soon Koo (Department of Internal Medicine, Yonsei University Wonju College of Medicine)
Publication Information
The Korean journal of internal medicine / v.33, no.3, 2018 , pp. 453-461 More about this Journal
Abstract
The renin-angiotensin system (RAS) is an important regulator of cirrhosis and portal hypertension. As hepatic fibrosis progresses, levels of the RAS components angiotensin (Ang) II, Ang-(1-7), angiotensin-converting enzyme (ACE), and Ang II type 1 receptor (AT1R) are increased. The primary effector Ang II regulates vasoconstriction, sodium homoeostasis, fibrosis, cell proliferation, and inflammation in various diseases, including liver cirrhosis, through the ACE/Ang II/AT1R axis in the classical RAS. The ACE2/Ang-(1-7)/Mas receptor and ACE2/Ang-(1-9)/AT2R axes make up the alternative RAS and promote vasodilation, antigrowth, proapoptotic, and anti-inflammatory effects; thus, countering the effects of the classical RAS axis to reduce hepatic fibrogenesis and portal hypertension. Patients with portal hypertension have been treated with RAS antagonists such as ACE inhibitors, Ang receptor blockers, and aldosterone antagonists, with very promising hemodynamic results. In this review, we examine the RAS, its roles in hepatic fibrosis and portal hypertension, and current therapeutic approaches based on the use of RAS antagonists in patients with portal hypertension.
Keywords
Renin-angiotensin system; Hepatic fibrosis; Hypertension; portal; Angiotensins; Receptors; angiotensin;
Citations & Related Records
Times Cited By KSCI : 7  (Citation Analysis)
연도 인용수 순위
1 Garcia-Tsao G, Bosch J. Management of varices and variceal hemorrhage in cirrhosis. N Engl J Med 2010;362:823-832.   DOI
2 Feu F, Garcia-Pagan JC, Bosch J, et al. Relation between portal pressure response to pharmacotherapy and risk of recurrent variceal haemorrhage in patients with cirrhosis. Lancet 1995;346:1056-1059.   DOI
3 Groszmann RJ, Garcia-Tsao G, Bosch J, et al. Beta-blockers to prevent gastroesophageal varices in patients with cirrhosis. N Engl J Med 2005;353:2254-2261.   DOI
4 Garcia-Pagan JC, Feu F, Navasa M, et al. Long-term haemodynamic effects of isosorbide 5-mononitrate in patients with cirrhosis and portal hypertension. J Hepatol 1990;11:189-195.   DOI
5 Albillos A, Lledo JL, Banares R, et al. Hemodynamic effects of alpha-adrenergic blockade with prazosin in cirrhotic patients with portal hypertension. Hepatology 1994;20:611-617.
6 Esler M, Dudley F, Jennings G, et al. Increased sympathetic nervous activity and the effects of its inhibition with clonidine in alcoholic cirrhosis. Ann Intern Med 1992;116:446-455.   DOI
7 Debernardi-Venon W, Martini S, Biasi F, et al. AT1 receptor antagonist Candesartan in selected cirrhotic patients: effect on portal pressure and liver fibrosis markers. J Hepatol 2007;46:1026-1033.
8 Schneider AW, Kalk JF, Klein CP. Effect of losartan, an angiotensin II receptor antagonist, on portal pressure in cirrhosis. Hepatology 1999;29:334-339.   DOI
9 Lavoie JL, Sigmund CD. Minireview: overview of the renin-angiotensin system: an endocrine and paracrine system. Endocrinology 2003;144:2179-2183.   DOI
10 Bataller R, Brenner DA. Liver fibrosis. J Clin Invest 2005;115:209-18.   DOI
11 Tox 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.   DOI
12 Kang SH, Kim MY, Baik SK. Novelties in the pathophysiology and management of portal hypertension: new treatments on the horizon. Hepatol Int 2018;12(Suppl 1):112-121.   DOI
13 Baik SK, Park DH, Kim MY, et al. Captopril reduces portal pressure effectively in portal hypertensive patients with low portal venous velocity. J Gastroenterol 2003;38:1150-1154.   DOI
14 Kim JH, Kim JM, Cho YZ, et al. Effects of candesartan and propranolol combination therapy versus propranolol monotherapy in reducing portal hypertension. Clin Mol Hepatol 2014;20:376-383.   DOI
15 Kim MY, Baik SK, Park DH, 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;43:889-896.   DOI
16 Heim MH, Jacob L, Beglinger C. The angiotensin II receptor antagonist candesartan is not effective in reducing portal hypertension in patients with cirrhosis. Digestion 2007;75:122-123.   DOI
17 De BK, Bandyopadhyay K, Das TK, et al. Portal pressure response to losartan compared with propranolol in patients with cirrhosis. Am J Gastroenterol 2003;98:1371-1376.   DOI
18 Kim MY, Cho MY, Baik SK, et al. Beneficial effects of candesartan, an angiotensin-blocking agent, on compensated alcoholic liver fibrosis: a randomized open-label controlled study. Liver Int 2012;32:977-987.   DOI
19 Abecasis R, Kravetz D, Fassio E, et al. Nadolol plus spironolactone in the prophylaxis of first variceal bleed in nonascitic cirrhotic patients: a preliminary study. Hepatology 2003;37:359-365.   DOI
20 Sugano S, Kawafune T, Okajima T, Ishii K, Watanabe M, Takamura N. Chronic splanchnic hemodynamic effects of spironolactone with unrestricted sodium diet in patients with compensated cirrhosis. Dig Dis Sci 1998;43:893-897.   DOI
21 Schepke M, Werner E, Biecker E, et al. Hemodynamic effects of the angiotensin II receptor antagonist irbesartan in patients with cirrhosis and portal hypertension. Gastroenterology 2001;121:389-395.   DOI
22 Henrion D, Kubis N, Levy BI. Physiological and pathophysiological functions of the AT(2) subtype receptor of angiotensin II: from large arteries to the microcirculation. Hypertension 2001;38:1150-1157.   DOI
23 Touyz RM, Schiffrin EL. Signal transduction mechanisms mediating the physiological and pathophysiological actions of angiotensin II in vascular smooth muscle cells. Pharmacol Rev 2000;52:639-672.
24 Tsochatzis EA, Bosch J, Burroughs AK. Liver cirrhosis. Lancet 2014;383:1749-1761.   DOI
25 Kim G, Shim KY, Baik SK. Diagnostic accuracy of hepatic vein arrival time performed with contrast-enhanced ultrasonography for cirrhosis: a systematic review and meta-analysis. Gut Liver 2017;11:93-101.   DOI
26 Bosch J, Abraldes JG, Fernandez M, Garcia-Pagan JC. Hepatic endothelial dysfunction and abnormal angiogenesis: new targets in the treatment of portal hypertension. J Hepatol 2010;53:558-567.   DOI
27 Kim MY, Baik SK. Hyperdynamic circulation in patients with liver cirrhosis and portal hypertension. Korean J Gastroenterol 2009;54:143-148.   DOI
28 Lichtinghagen R, Michels D, Haberkorn CI, et al. 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 2001;34:239-247.   DOI
29 Baik SK, Jo HS, Suk KT, et al. Inhibitory effect of angiotensin II receptor antagonist on the contraction and growth of hepatic stellate cells. Korean J Gastroenterol 2003;42:134-141.
30 Paizis G, Tikellis C, Cooper ME, et al. Chronic liver injury in rats and humans upregulates the novel enzyme angiotensin converting enzyme 2. Gut 2005;54:1790-1796.   DOI
31 Herath CB, Warner FJ, Lubel JS, et al. Upregulation of hepatic angiotensin-converting enzyme 2 (ACE2) and angiotensin-(1-7) levels in experimental biliary fibrosis. J Hepatol 2007;47:387-395.   DOI
32 Rockey D. The cellular pathogenesis of portal hypertension: stellate cell contractility, endothelin, and nitric oxide. Hepatology 1997;25:2-5.   DOI
33 Kaneda K, Ekataksin W, Sogawa M, Matsumura A, Cho A, Kawada N. Endothelin-1-induced vasoconstriction causes a significant increase in portal pressure of rat liver: localized constrictive effect on the distal segment of preterminal portal venules as revealed by light and electron microscopy and serial reconstruction. Hepatology 1998;27:735-747.   DOI
34 Bhathal PS, Grossman HJ. Reduction of the increased portal vascular resistance of the isolated perfused cirrhotic rat liver by vasodilators. J Hepatol 1985;1:325-337.   DOI
35 Terui Y, Saito T, Watanabe H, et al. Effect of angiotensin receptor antagonist on liver fibrosis in early stages of chronic hepatitis C. Hepatology 2002;36(4 Pt 1):1022.   DOI
36 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 2002;123:1667-1676.   DOI
37 Bataller R, Sancho-Bru P, Gines P, et al. Activated human hepatic stellate cells express the renin-angiotensin system and synthesize angiotensin II. Gastroenterology 2003;125:117-125.   DOI
38 Sakata T, Takenaga N, Endoh T, Wada O, Matsuki K. Diagnostic significance of serum angiotensin-converting enzyme activity in biochemical tests with special reference of chronic liver diseases. Jpn J Med 1991;30:402-407.   DOI
39 Bataller R, Gines P, Nicolas JM, et al. Angiotensin II induces contraction and proliferation of human hepatic stellate cells. Gastroenterology 2000;118:1149-1156.   DOI
40 Yokohama S, Tokusashi Y, Nakamura K, et al. Inhibitory effect of angiotensin II receptor antagonist on hepatic stellate cell activation in non-alcoholic steatohepatitis. World J Gastroenterol 2006;12:322-326.   DOI
41 Sookoian S, Fernandez MA, Castano G. Effects of six months losartan administration on liver fibrosis in chronic hepatitis C patients: a pilot study. World J Gastroenterol 2005;11:7560-7563.   DOI
42 Rimola A, Londono MC, Guevara G, et al. Beneficial effect of angiotensin-blocking agents on graft fibrosis in hepatitis C recurrence after liver transplantation. Transplantation 2004;78:686-691.
43 Corey KE, Shah N, Misdraji J, et al. The effect of angiotensin-blocking agents on liver fibrosis in patients with hepatitis C. Liver Int 2009;29:748-753.   DOI
44 Colmenero J, Bataller R, Sancho-Bru P, et al. Effects of losartan on hepatic expression of nonphagocytic NADPH oxidase and fibrogenic genes in patients with chronic hepatitis C. Am J Physiol Gastrointest Liver Physiol 2009;297:G726-G734.   DOI
45 Abu Dayyeh BK, Yang M, Dienstag JL, Chung RT. The effects of angiotensin blocking agents on the progression of liver fibrosis in the HALT-C trial cohort. Dig Dis Sci 2011;56:564-568.   DOI
46 Goh GB, Pagadala MR, Dasarathy J, et al. Renin-angiotensin system and fibrosis in non-alcoholic fatty liver disease. Liver Int 2015;35:979-985.   DOI
47 Zhu Q, Li N, Li F, et al. Therapeutic effect of renin angiotensin system inhibitors on liver fibrosis. J Renin Angiotensin Aldosterone Syst 2016;17:1470320316628717.
48 Eom YW, Shim KY, Baik SK. Mesenchymal stem cell therapy for liver fibrosis. Korean J Intern Med 2015;30:580-589.   DOI
49 Peiro C, Vallejo S, Gembardt F, et al. Endothelial dysfunction through genetic deletion or inhibition of the G protein-coupled receptor Mas: a new target to improve endothelial function. J Hypertens 2007;25:2421-2425.   DOI
50 Kim G, Kim MY, Baik SK. Transient elastography versus hepatic venous pressure gradient for diagnosing portal hypertension: a systematic review and meta-analysis. Clin Mol Hepatol 2017;23:34-41.   DOI
51 Grace JA, Herath CB, Mak KY, Burrell LM, Angus PW. Update on new aspects of the renin-angiotensin system in liver disease: clinical implications and new therapeutic options. Clin Sci (Lond) 2012;123:225-239.   DOI
52 Dickstein K, Kjekshus J; OPTIMAAL Steering Committee of the OPTIMAAL Study Group. Effects of losartan and captopril on mortality and morbidity in high-risk patients after acute myocardial infarction: the OPTIMAAL randomised trial. Optimal Trial in Myocardial Infarction with Angiotensin II Antagonist Losartan. Lancet 2002;360:752-760.   DOI
53 Kim G, Kim J, Lim YL, Kim MY, Baik SK. Renin-angiotensin system inhibitors and fibrosis in chronic liver disease: a systematic review. Hepatol Int 2016;10:819-828.   DOI
54 Lim YL, Choi E, Jang YO, et al. Clinical implications of the serum apelin level on portal hypertension and prognosis of liver cirrhosis. Gut Liver 2016;10:109-116.   DOI
55 Kim G, Eom YW, Baik SK, et al. Therapeutic effects of mesenchymal stem cells for patients with chronic liver diseases: systematic review and meta-analysis. J Korean Med Sci 2015;30:1405-1415.   DOI
56 Lubel JS, Herath CB, Burrell LM, Angus PW. Liver disease and the renin-angiotensin system: recent discoveries and clinical implications. J Gastroenterol Hepatol 2008;23:1327-1338.   DOI
57 Suzuki Y, Ruiz-Ortega M, Lorenzo O, Ruperez M, Esteban V, Egido J. Inflammation and angiotensin II. Int J Biochem Cell Biol 2003;35:881-900.   DOI
58 Ruiz-Ortega M, Lorenzo O, Suzuki Y, Ruperez M, Egido J. Proinflammatory actions of angiotensins. Curr Opin Nephrol Hypertens 2001;10:321-329.   DOI
59 Jang YO, Cho MY, Yun CO, et al. Effect of function-enhanced mesenchymal stem cells infected with decorin-expressing adenovirus on hepatic fibrosis. Stem Cells Transl Med 2016;5:1247-1256.   DOI
60 Bataller R, Schwabe RF, Choi YH, 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.   DOI
61 Moreno-Alvarez P, Sosa-Garrocho M, Briones-Orta MA, et al. Angiotensin II increases mRNA levels of all TGF-beta isoforms in quiescent and activated rat hepatic stellate cells. Cell Biol Int 2010;34:969-978.   DOI
62 Lubel JS, Herath CB, Tchongue J, 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;117:375-386.   DOI
63 Pereira RM, Dos Santos RA, Teixeira MM, 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;46:674-681.   DOI
64 Suk KT, Yoon JH, Kim MY, et al. Transplantation with autologous bone marrow-derived mesenchymal stem cells for alcoholic cirrhosis: phase 2 trial. Hepatology 2016;64:2185-2197.   DOI
65 Burrell LM, Risvanis J, Kubota E, et al. Myocardial infarction increases ACE2 expression in rat and humans. Eur Heart J 2005;26:369-375.   DOI
66 Osterreicher CH, Taura K, De Minicis S, et al. Angiotensin-converting-enzyme 2 inhibits liver fibrosis in mice. Hepatology 2009;50:929-938.
67 Marrero MB, Schieffer B, Paxton WG, et al. Direct stimulation of Jak/STAT pathway by the angiotensin II AT1 receptor. Nature 1995;375:247-250.   DOI
68 Kagami S, Border WA, Miller DE, Noble NA. Angiotensin II stimulates extracellular matrix protein synthesis through induction of transforming growth factor-beta expression in rat glomerular mesangial cells. J Clin Invest 1994;93:2431-2437.   DOI
69 Hunyady L, Catt KJ. Pleiotropic AT1 receptor signaling pathways mediating physiological and pathogenic actions of angiotensin II. Mol Endocrinol 2006;20:953-970.   DOI
70 Albornoz L, Motta A, Alvarez D, et al. Nitric oxide synthase activity in the splanchnic vasculature of patients with cirrhosis: relationship with hemodynamic disturbances. J Hepatol 2001;35:452-456.   DOI
71 Mehta PK, Griendling KK. Angiotensin II cell signaling: physiological and pathological effects in the cardiovascular system. Am J Physiol Cell Physiol 2007;292:C82-C97.   DOI
72 de Gasparo M, Catt KJ, Inagami T, Wright JW, Unger T. International union of pharmacology. XXIII. The angiotensin II receptors. Pharmacol Rev 2000;52:415-472.
73 Dinh DT, Frauman AG, Johnston CI, Fabiani ME. Angiotensin receptors: distribution, signalling and function. Clin Sci (Lond) 2001;100:481-492.   DOI
74 Griendling KK, Alexander RW. The angiotensin (AT1) receptor. Semin Nephrol 1993;13:558-566.
75 Schieffer B, Paxton WG, Marrero MB, Bernstein KE. Importance of tyrosine phosphorylation in angiotensin II type 1 receptor signaling. Hypertension 1996;27(3 Pt 2):476-480.   DOI
76 Nguyen G, Delarue F, Burckle C, Bouzhir L, Giller T, Sraer JD. Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular responses to renin. J Clin Invest 2002;109:1417-1427.   DOI
77 Mezzano SA, Ruiz-Ortega M, Egido J. Angiotensin II and renal fibrosis. Hypertension 2001;38(3 Pt 2):635-638.   DOI
78 Tandon P, Abraldes JG, Berzigotti A, Garcia-Pagan JC, Bosch J. Renin-angiotensin-aldosterone inhibitors in the reduction of portal pressure: a systematic review and meta-analysis. J Hepatol 2010;53:273-282.   DOI
79 Sieber CC, Lopez-Talavera JC, Groszmann RJ. Role of nitric oxide in the in vitro splanchnic vascular hyporeactivity in ascitic cirrhotic rats. Gastroenterology 1993;104:1750-1754.   DOI
80 Kim G, Cho YZ, Baik SK. Assessment for risk of bias in systematic reviews and meta-analyses in the field of hepatology. Gut Liver 2015;9:701-706.   DOI
81 Park DH, Baik SK, Choi YH, et al. Inhibitory effect of angiotensin blockade on hepatic fibrosis in common bile duct-ligated rats. Korean J Hepatol 2007;13:61-69.
82 Angus PW. Role of endothelin in systemic and portal resistance in cirrhosis. Gut 2006;55:1230-1232.   DOI
83 Kim G, Huh JH, Lee KJ, Kim MY, Shim KY, Baik SK. Relative adrenal insufficiency in patients with cirrhosis: a systematic review and meta-analysis. Dig Dis Sci 2017;62:1067-1079.   DOI
84 Feldt S, Batenburg WW, Mazak I, et al. Prorenin and renin-induced extracellular signal-regulated kinase 1/2 activation in monocytes is not blocked by aliskiren or the handle-region peptide. Hypertension 2008;51:682-688.   DOI
85 Yoshiji H, Noguchi R, Ikenaka Y, et al. Losartan, an angiotensin-II type 1 receptor blocker, attenuates the liver fibrosis development of non-alcoholic steatohepatitis in the rat. BMC Res Notes 2009;2:70.   DOI
86 Ferrario CM, Trask AJ, Jessup JA. Advances in biochemical and functional roles of angiotensin-converting enzyme 2 and angiotensin-(1-7) in regulation of cardiovascular function. Am J Physiol Heart Circ Physiol 2005;289:H2281-H2290.   DOI
87 Lebrec D, Nouel O, Corbic M, Benhamou JP. Propranolol: a medical treatment for portal hypertension? Lancet 1980;2:180-182.
88 Tripathi D, Hayes PC. Beta-blockers in portal hypertension: new developments and controversies. Liver Int 2014;34:655-667.   DOI
89 Crackower MA, Sarao R, Oudit GY, et al. Angiotensin-converting enzyme 2 is an essential regulator of heart function. Nature 2002;417:822-828.   DOI
90 Donoghue M, Hsieh F, Baronas E, et al. A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9. Circ Res 2000;87:E1-E9.   DOI
91 Vickers C, Hales P, Kaushik V, et al. Hydrolysis of biological peptides by human angiotensin-converting enzyme-related carboxypeptidase. J Biol Chem 2002;277:14838-14843.   DOI
92 Villela DC, Passos-Silva DG, Santos RA. Alamandine: a new member of the angiotensin family. Curr Opin Nephrol Hypertens 2014;23:130-134.   DOI
93 Santos RA, Simoes e Silva AC, Maric C, et al. Angiotensin-(1-7) is an endogenous ligand for the G protein-coupled receptor Mas. Proc Natl Acad Sci U S A 2003;100:8258-8263.   DOI
94 Lima CV, Paula RD, Resende FL, Khosla MC, Santos RA. Potentiation of the hypotensive effect of bradykinin by short-term infusion of angiotensin-(1-7) in normotensive and hypertensive rats. Hypertension 1997;30(3 Pt 2):542-548.   DOI
95 Tallant EA, Clark MA. Molecular mechanisms of inhibition of vascular growth by angiotensin-(1-7). Hypertension 2003;42:574-579.   DOI
96 Poynard T, Cales P, Pasta L, et al. Beta-adrenergic-antagonist drugs in the prevention of gastrointestinal bleeding in patients with cirrhosis and esophageal varices: an analysis of data and prognostic factors in 589 patients from four randomized clinical trials. Franco-Italian Multicenter Study Group. N Engl J Med 1991;324:1532-1538.   DOI