Renin-angiotensin system inhibitors as therapeutic alternatives in the treatment of chronic liver diseases.
The renin-angiotensin system (RAS) is frequently activated in the patients with chronic liver diseases, and recent studies have shown that RAS plays a pivotal role in the progression of chronic liver diseases, i.e., liver fibrosis and hepatocellular carcinoma (HCC). Angiotensin-II (AT-II) reportedly stimulates contractility and proliferation of the activated hepatic stellate cells, and increases the transforming growth factor-beta (TGF-betabeta expression through angiotensin type-I receptors (AT1-R). Many studies have demonstrated that the clinically used angiotensin-converting enzyme inhibitors (ACE-I) and AT1-R blockers (ARB) significantly attenuated the liver fibrosis development in the experimental studies and clinical practice. AT-II also strongly promotes neovascularization, which plays a pivotal role in tumor development. AT-II induces a potent angiogenic factor; namely, the vascular endothelial growth factor (VEGF). It has been reported that ACE-I significantly attenuated the experimental HCC growth and hepatocarcinogenesis along with suppression of neovascularization. The VEGF expression in the tumor was suppressed by ACE-I, too. The combined treatment of ACE-I with other clinically used agents, such as interferon, imatinib mesylate, and vitamin K, shows more potent inhibitory effects on the development of liver fibrosis and HCC. Since RAS inhibitors are widely used in the clinical practice without serious side effects, they may represent a potential new therapeutic strategy against the progression of chronic liver diseases.
Third Department of Internal Medicine, Nara Medical University, Nara, Japan. yoshijih@naramed-u.ac.jp
Hitoshi
H
Yoshiji
Ryuichi
R
Noguchi
Yasuhide
Y
Ikenaka
Mitsuteru
M
Kitade
Kosuke
K
Kaji
Tatsuhiro
T
Tsujimoto
Masahito
M
Uemura
Hiroshi
H
Fukui
D000804:Angiotensin II / Q000378:metabolism*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000378:metabolism / Q000627:therapeutic use*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000378:metabolism / Q000627:therapeutic use*; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D008103:Liver Cirrhosis / Q000188:drug therapy* / Q000378:metabolism; D008113:Liver Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism; D018919:Neovascularization, Physiologic; D012084:Renin-Angiotensin System / Q000187:drug effects* / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D042461:Vascular Endothelial Growth Factor A; D000804:Angiotensin II