Anti-fibrogenic function of angiotensin II type 2 receptor in CCl4-induced liver fibrosis.
The renin-angiotensin system (RAS) contributes to fibrogenesis in a variety of organs. We recently showed that a lack of angiotensin (Ang) II type 1 (AT1) receptor activity reduces liver fibrosis. In this study, we investigated whether the Ang II type 2 (AT2) receptor is implicated in the development of liver fibrosis. A comparison was made between AT2-receptor knockout (AT2KO) and wild type (WT) mice after 4 weeks of treatment with carbon tetrachloride (CCl4). Fibrosis was assessed by Azan-Mallory staining and hepatic hydroxyproline (HP) content. The expression of fibrogenic mRNA was measured by real-time quantitative reverse-transcription polymerase chain reaction (PCR). Liver fibrosis evaluated by regular histological analyses and immunohistochemical alpha-SMA staining was observed in both groups of mice. The extent of fibrosis was greatest in the AT2KO mice. Fibrosis was associated with increases in hepatic HP content and mRNA expression for TGF-beta1 and alpha-SMA, as well as an increase in hepatic TBARS. These findings suggest that CCl4 induces oxidative stress which leads to activation of hepatic stellate cells (HSCs). These changes were considerably more pronounced in the AT2KO mice than the WT mice. Taken together, we conclude that AT2 signal has anti-fibrogenic and/or cytoprotective effects on oxidative stress-induced liver fibrosis. We therefore suggest that RAS-associated liver fibrogenesis may be determined by the balance between AT1 and AT2 signals.
Nabeshima
Yoshitaka
Y
Department of Medicine and Molecular Science, Graduate School of Biomedical Sciences, Hiroshima University 1-2-3, Kasumi, Minami-ku, Hiroshima 734-8551, Japan.
Tazuma
Susumu
S
Kanno
Keishi
K
Hyogo
Hideyuki
H
Iwai
Masaru
M
Horiuchi
Masatsugu
M
Chayama
Kazuaki
K
D000818:Animals; D002251:Carbon Tetrachloride / Q000008:administration & dosage / Q000494:pharmacology*; D005786:Gene Expression Regulation; D006909:Hydroxyproline / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics; D044139:Receptor, Angiotensin, Type 2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics
D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D017392:Thiobarbituric Acid Reactive Substances; D016212:Transforming Growth Factor beta; D002251:Carbon Tetrachloride; D006909:Hydroxyproline