Rho-kinase inhibitor prevents hepatocyte damage in acute liver injury induced by carbon tetrachloride in rats.
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.
Ikeda
Hitoshi
H
Dept. of Laboratory Medicine, The Univ. of Tokyo, 7-3-1 Hongo, Tokyo 113-8655, Japan. ikeda-1im@h.u-tokyo.ac.jp
Kume
Yukio
Y
Tejima
Kazuaki
K
Tomiya
Tomoaki
T
Nishikawa
Takako
T
Watanabe
Naoko
N
Ohtomo
Natsuko
N
Arai
Masahiro
M
Arai
Chihiro
C
Omata
Masao
M
Fujiwara
Kenji
K
Yatomi
Yutaka
Y
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*
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