A selective ROCK inhibitor, Y27632, prevents dimethylnitrosamine-induced hepatic fibrosis in rats.
BACKGROUND
p160ROCK is a direct Rho target which mediates Rho-induced assembly of focal adhesions and stress fibers. We previously reported that Rho signaling pathways are involved in the activation of hepatic stellate cells (HSC) in vitro. The aim of the present study was to test the hypothesis that an inhibitor specific for p160ROCK (Y27632) could prevent experimental hepatic fibrosis induced by dimethylnitrosamine (DMN) in rats.


METHODS
Y27632 was given orally at 30 mg/kg daily for 4 weeks after the first injection of DMN. The degree of fibrosis was evaluated by image analysis and also by measurements of collagen and hydroxyproline content in the liver. The expression of alpha-smooth muscle actin (alpha-SMA) in the liver and in the primary cultured HSC was also evaluated. Semi-quantitative RT-PCR was performed to evaluate the expression of type I collagen mRNA in the liver.


RESULTS
Y27632 treatment significantly decreased the occurrence of DMN-induced hepatic fibrosis and reduced the collagen and hydroxyproline content and alpha-SMA expression in the liver. The expression of alpha-SMA in HSC was also suppressed in vitro.


CONCLUSIONS
These findings indicate that inhibitors of the Rho-ROCK pathway might be useful therapeutically in hepatic fibrosis.
Tada
S
S
Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Iwamoto
H
H
Nakamuta
M
M
Sugimoto
R
R
Enjoji
M
M
Nakashima
Y
Y
Nawata
H
H
D000199:Actins / Q000037:antagonists & inhibitors; D000577:Amides / Q000494:pharmacology*; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003094:Collagen / Q000037:antagonists & inhibitors / Q000235:genetics; D004128:Dimethylnitrosamine / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006909:Hydroxyproline / Q000037:antagonists & inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D009130:Muscle, Smooth / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000037:antagonists & inhibitors; D051381:Rats; D017208:Rats, Wistar; D054460:rho-Associated Kinases
D000199:Actins; D000577:Amides; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D011725:Pyridines; D012333:RNA, Messenger; C108830:Y 27632; D003094:Collagen; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D004128:Dimethylnitrosamine; D006909:Hydroxyproline