An angiotensin II type 1 receptor antagonist, olmesartan medoxomil, improves experimental liver fibrosis by suppression of proliferation and collagen synthesis in activated hepatic stellate cells.
1. We studied the effect of a new angiotensin II type 1 (AT(1)) receptor antagonist, olmesartan medoxomil (olmesartan), on the fibrogenic responses in rat hepatic stellate cells (HSCs) and liver fibrogenesis. 2. Olmesartan (1 mg kg(-1) per day) was orally administered to fibrotic rats, induced by bile duct ligation. Liver hydroxyproline content, the mRNA expression of collagen alpha1(I) and alpha-smooth muscle actin (alpha-SMA), and plasma levels of transforming growth factor-beta1 (TGF-beta1) were significantly reduced by olmesartan treatment, suggesting that olmesartan improved liver fibrosis. Interestingly, AT(1) receptors were found to be expressed in alpha-SMA-positive cells in the fibrotic area of livers in bile duct-ligated rats by immunohistochemical analysis. Olmesartan treatment reduced the number of these cells. 3. In vitro experiments showed that angiotensin II (Ang II) treatment induced proliferation and collagen synthesis, and upregulated the profibrogenic cytokines, TGF-beta1 and connective tissue growth factor (CTGF), in rat primary HSCs. Olmesartan blocked all these effects of Ang II. 4. Based on these results, since activated HSCs were found to express AT(1) receptors and Ang II is thought to play an important role in the pathogenesis of liver fibrosis by binding to these receptors, olmesartan may act as a potent antifibrotic drug to suppress the proliferation, collagen synthesis and the expression of profibrogenic cytokines in activated HSCs by blocking these receptors.
Kurikawa
Nobuya
N
Pharmacology and Molecular Biology Research Laboratories, Sankyo Co., Ltd, 2-58, Hiromachi 1-chome, Shinagawa-ku, Tokyo 140-8710, Japan. kurikuri@shina.sankyo.co.jp
Suga
Miwa
M
Kuroda
Shoko
S
Yamada
Keisuke
K
Ishikawa
Hirokazu
H
D047228:Angiotensin II Type 1 Receptor Blockers; D000818:Animals; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D003094:Collagen / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D008103:Liver Cirrhosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D000068557:Olmesartan Medoxomil; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology / Q000627:therapeutic use*
D047228:Angiotensin II Type 1 Receptor Blockers; D007093:Imidazoles; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D000068557:Olmesartan Medoxomil; D003094:Collagen