title: Rho/Rho kinase is a key enzyme system involved in the angiotensin II signaling pathway of liver fibrosis and steatosis.
abstract: OBJECTIVE
  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-alpha 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-beta and alpha-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-alpha 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-beta and alpha-smooth muscle actin stimulated by angiotensin II was also significantly suppressed by these two drugs.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan.
authors.forename: Kumi
authors.initials: K
authors.lastname: Kitamura
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Tada
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Nakamoto
authors.forename: Kyoko
authors.initials: K
authors.lastname: Toda
authors.forename: Hitomi
authors.initials: H
authors.lastname: Horikawa
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kurita
authors.forename: Satoshi
authors.initials: S
authors.lastname: Tsunematsu
authors.forename: Naoki
authors.initials: N
authors.lastname: Kumagai
authors.forename: Hiromasa
authors.initials: H
authors.lastname: Ishii
authors.forename: Hidetsugu
authors.initials: H
authors.lastname: Saito
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Hibi
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000577:Amides / Q000494:pharmacology / Q000627:therapeutic use; D000804:Angiotensin II / Q000378:metabolism*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D001562:Benzimidazoles / Q000494:pharmacology / Q000627:therapeutic use; D001713:Biphenyl Compounds / Q000494:pharmacology / Q000627:therapeutic use; D002478:Cells, Cultured; D002796:Choline Deficiency / Q000150:complications* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D004249:DNA Damage; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000188:drug therapy / Q000201:enzymology / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D008103:Liver Cirrhosis / Q000188:drug therapy / Q000201:enzymology / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D009929:Organ Size; D018384:Oxidative Stress; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013777:Tetrazoles / Q000494:pharmacology / Q000627:therapeutic use; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000378:metabolism*; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000577:Amides; D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D013777:Tetrazoles; D014409:Tumor Necrosis Factor-alpha; D000804:Angiotensin II; C108830:Y 27632; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D054460:rho-Associated Kinases; D020741:rho GTP-Binding Proteins; C077793:candesartan cilexetil