Rho/Rho kinase is a key enzyme system involved in the angiotensin II signaling pathway of liver fibrosis and steatosis

Kumi Kitamura, Shinichiro Tada, Nobuhiro Nakamoto, Kyoko Toda, Hitomi Horikawa, Satoshi Kurita, Satoshi Tsunematsu, Naoki Kumagai, Hiromasa Ishii, Hidetsugu Saito, Toshifumi Hibi

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Abstract

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.

Original languageEnglish
Pages (from-to)2022-2033
Number of pages12
JournalJournal of Gastroenterology and Hepatology (Australia)
Volume22
Issue number11
DOIs
Publication statusPublished - 2007 Nov

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Keywords

  • Free radical
  • Hepatic fibrosis
  • Hepatic stellate cells
  • Renin-angiotensin system
  • Rho/Rho kinase system

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

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