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.

The effect of Rho kinase inhibitor Y-27632 on endotoxemia-induced intestinal apoptosis in infant rats

“…As mentioned above, Rho kinase demonstrated to play a regulatory role for apoptosis of various cell types (Shi and Wei 2007). While Rho-kinase inhibition enhanced apoptosis in smooth muscle cells (Shibata et al 2001) or endothelial cells (Li et al 2002), Rho-kinase inhibition reduced apoptosis in myocytes (Bao et al 2004), vascular wall (Wang et al 2005) or hepatocytes (Ikeda et al 2007). In the present study, we found that Rho kinase inhibitor attenuated intestinal apoptosis induced by endotoxemia in infant rats.…”

“…In the present study, we found that Rho kinase inhibitor attenuated intestinal apoptosis induced by endotoxemia in infant rats. The pro-and anti-apoptotic effects of Rho kinase inhibition seems to depend on cell types (Ikeda et al 2007). The mechanism to explain this distinct effect should be further clear up.…”

Naringenin-Loaded Nanoparticles Improve the Physicochemical Properties and the Hepatoprotective Effects of Naringenin in Orally-Administered Rats with CCl4-Induced Acute Liver Failure

“…Intoxication with CCl 4 not only overproduces the ROS to exhaust cellular SOD, CAT, and GPx (47,48), but also results in ROS attacks on unsaturated fatty acids of phospholipids in the hepatocyte membrane to subsequently begin a chain reaction of lipid peroxidation (8,10). The ensuing oxidative stress from CCl 4 -intoxication could disrupt the structural integrity of the hepatic cell membrane and lead to leakage of AST and ALT hepatic cellular enzymes into the blood from dead hepatocytes, thus producing signs of hepatotoxicity (49,50). Several studies have demonstrated that antioxidant supplements may be an excellent prevention strategy for many diseases, including liver injury, liver fibrosis, aging, cancer, and diabetes (51).…”

Hepatoprotective effect and its possible mechanism of Coptidis rhizoma aqueous extract on carbon tetrachloride-induced chronic liver hepatotoxicity in rats

“…Isolated cells were cultured in Williams' medium E (WME, Sigma-Aldrich, USA) supplemented with 10% FBC (Invitrogen, USA), 0.9 M dexamethasone (Sigma-Aldrich, USA) and 10 M insulin (Sigma-Aldrich, USA). Medium was replaced with serum-and hormone-free WME (Ikeda et al, 2007).…”