Blockade of renin-angiotensin system in antifibrotic therapy.
Recent studies have shown that the renin-angiotensin system (RAS) plays a pivotal role in liver fibrosis. An intrahepatic RAS is expressed in chronically damaged livers, and angiotensin-II (AT-II) reportedly stimulates contraction and proliferation of the activated hepatic stellate cells (Ac-HSC), and increases the transforming growth factor-beta (TGF-beta) expression through angiotensin type-I receptors (AT1-R). Some studies have demonstrated that the clinically used angiotensin-converting enzyme (ACE) inhibitor (ACE-I), and AT1-R blockers (ARB) significantly attenuated experimental liver fibrosis along with suppression of the Ac-HSC and hepatic TGF-beta expression. Angiotensin-II also stimulates the tissue inhibitor of metalloproteinases-1 (TIMP-1) in a dose- and time-dependent manner via protein kinase-C as an intracellular signaling cascade in the Ac-HSC, and these effects are completely suppressed by ARB. Combination treatment with low-dose interferon (IFN) and ACE-I exerts a stronger inhibitory effect than either single agent on its own. In humans it has been reported that ARB markedly improved the liver fibrosis score and TGF-beta expression in patients with chronic hepatitis C and non-alcoholic steatohepatitis. Serum fibrosis markers also significantly improved by treatment with low-dose IFN and ACE-I in patients with chronic hepatitis C, refractory to IFN monotherapy. Collectively, these data suggest that the interaction between AT-II and AT1-R plays a pivotal role in liver fibrosis development. Because both ACE-I and ARB are widely used in clinical practice without serious side-effects, these drugs in combination with IFN may provide a new strategy for antifibrosis therapy.
Yoshiji
Hitoshi
H
Third Department of Internal Medicine, Nara Medical University, Nara, Japan. yoshijih@naramed-u.ac.jp
Kuriyama
Shigeki
S
Fukui
Hiroshi
H
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D008103:Liver Cirrhosis / Q000188:drug therapy*; D012084:Renin-Angiotensin System / Q000187:drug effects*; D019714:Tissue Inhibitor of Metalloproteinases / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors
D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D019714:Tissue Inhibitor of Metalloproteinases; D042461:Vascular Endothelial Growth Factor A