Background and Aim: The molecular mechanisms underlying the involvement of the renin-angiotensin system in hepatic fibrosis are unclear. Recently, it was reported that a Rho kinase inhibitor prevented fibrosis of various tissues and that the Rho/Rho kinase pathway was involved in the renin-angiotensin system of vascular smooth muscle cells. In this study, the involvement of the Rho/Rho kinase pathway on angiotensin II signaling in liver fibrogenesis and generation of steatosis was investigated. Methods: Rats were fed a choline-deficient/L- amino acid-defined (CDAA) diet continuously and treated with a Rho kinase inhibitor, Y-27632, and an angiotensin II receptor blocker, TCV-116. Liver histology and hepatic stellate cell activation were analyzed. Free radical production was detected by 4-hydroxynonenal and 8-hydroxy-2′- deoxyguanosine immunostaining and the expression of tumor necrosis factor-α was examined. Isolated hepatic stellate cells were pretreated with a Rho kinase inhibitor, Y-27632, or an angiotensin II receptor blocker, CV-11974, and stimulated with angiotensin II, and mRNA expression of transforming growth factor-β and α-smooth muscle actin was analyzed. Results: Both the angiotensin II receptor blocker and the Rho kinase inhibitor improved fibrosis and steatosis of the liver in CDAA-fed rats. The increase in the number of hepatocytes positive for 4-hydroxynonenal and 8-hydroxy-2′- deoxyguanosine in CDAA-fed rats was significantly prevented by the angiotensin II receptor blocker and the Rho kinase inhibitor. The levels of tumor necrosis factor-α mRNA in the liver of CDAA-fed rats were significantly increased and this increase was significantly inhibited by treatment with the angiotensin II receptor blocker and the Rho kinase inhibitor. mRNA expression of transforming growth factor-β and α-smooth muscle actin stimulated by angiotensin II was also significantly suppressed by these two drugs. Conclusion: These results suggest that the Rho/Rho kinase pathway is at least partly involved in the renin-angiotensin system and plays an important role in hepatic fibrosis and steatosis.
|Journal of Gastroenterology and Hepatology (Australia)
|Published - 2007 11月
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