title: Rho-kinase inhibitor prevents hepatocyte damage in acute liver injury induced by carbon tetrachloride in rats.
abstract: A protective effect of Rho-kinase inhibitor on various organ injuries is gaining attention. Regarding liver injury, Rho-kinase inhibitor is reported to prevent carbon tetrachloride (CCl4)- or dimethylnitrosamine-induced liver fibrosis and hepatic ischemia-reperfusion injury in rats. Because Rho-kinase inhibitor not only improved liver fibrosis but also reduced serum alanine aminotransferase (ALT) level in CCl4-induced liver fibrosis, we wondered whether Rho-kinase inhibitor might exert a direct hepatocyte-protective effect. We examined this possibility in acute CCl4 intoxication in rats. Rho-kinase inhibitor, HA-1077, reduced serum alanine ALT level in rats with acute liver injury induced by CCl4 with the improvement of histological damage and the reduction of the number of apoptotic cells. In cultured rat hepatocytes in serum-free condition, HA-1077 reduced apoptosis evaluated by quantitative determination of cytoplasmic histone-associated DNA oligonucleosome fragments with the reduction of caspase-3 activity and the enhancement of Bcl-2 expression. HA-1077 stimulated phosphorylation of Akt, and wortmannin, an inhibitor of phosphatidylinositol 3-kinase (PI3-kinase)/Akt pathway, abrogated the reduction of hepatocyte apoptosis by HA-1077 in vitro. Furthermore, wortmannin abrogated the reduction of serum ALT level by HA-1077 in rats with acute liver injury induced by CCl4, suggesting that the activation of PI3-kinase/Akt pathway may be involved in the hepatocyte-protective effect by Rho-kinase inhibitor in vivo. In conclusion, Rho-kinase inhibitor prevented hepatocyte damage in acute liver injury induced by CCl4 in rats and merits consideration as a hepatocyte-protective agent in liver injury, considering its direct antiapoptotic effect on hepatocytes in vitro.
authors.affiliation: Dept. of Laboratory Medicine, The Univ. of Tokyo, 7-3-1 Hongo, Tokyo 113-8655, Japan. ikeda-1im@h.u-tokyo.ac.jp
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Ikeda
authors.forename: Yukio
authors.initials: Y
authors.lastname: Kume
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Tejima
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Tomiya
authors.forename: Takako
authors.initials: T
authors.lastname: Nishikawa
authors.forename: Naoko
authors.initials: N
authors.lastname: Watanabe
authors.forename: Natsuko
authors.initials: N
authors.lastname: Ohtomo
authors.forename: Masahiro
authors.initials: M
authors.lastname: Arai
authors.forename: Chihiro
authors.initials: C
authors.lastname: Arai
authors.forename: Masao
authors.initials: M
authors.lastname: Omata
authors.forename: Kenji
authors.initials: K
authors.lastname: Fujiwara
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Yatomi
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002252:Carbon Tetrachloride Poisoning / Q000188:drug therapy* / Q000473:pathology; D056486:Chemical and Drug Induced Liver Injury; D053938:DNA Fragmentation / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects*; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008107:Liver Diseases / Q000188:drug therapy*; D008297:Male; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077191:Wortmannin; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000730:Androstadienes; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D054460:rho-Associated Kinases; C049347:fasudil; D000077191:Wortmannin