Overexpression of NK2 promotes liver fibrosis in carbon tetrachloride-induced chronic liver injury.
OBJECTIVE
Hepatocyte growth factor (HGF) inhibits liver fibrosis induced by carbon tetrachloride (CCl4) in animal models. NK2 is a natural splice variant of HGF, but its in vivo function remains to be elucidated. We investigated the in vivo effects of NK2 on CCl4-induced liver fibrosis.


METHODS
NK2 transgenic mice and wild-type (WT) mice were injected intraperitoneally with CCl4 twice a week. The extent of hepatic fibrosis was evaluated by Azan-Mallory staining. Expression levels of mRNAs of transforming growth factor-beta1 (TGF-beta1) and matrix metalloproteinase-13 (MMP-13) were examined by real-time polymerase chain reaction. The protein levels of alpha-smooth muscle actin (alpha-SMA), c-Met and its phosphorylation were determined by Western blot analysis.


RESULTS
Liver fibrosis was significantly more severe in NK2 transgenic mice than in WT mice. CCl4 administration increased the expression levels of TGF-beta1 mRNA and alpha-SMA protein, and decreased the expression of MMP-13 mRNA in livers of NK2 transgenic mice compared with those of WT mice. c-Met protein expression in the liver was compatible with the degree of fibrosis. As for c-Met activation, no difference was found between NK2 and WT livers.


CONCLUSIONS
Overexpression of NK2 acts as an antagonist of HGF and promotes liver fibrosis in CCl4-induced chronic liver injury.
Hagiwara
Satoshi
S
Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.
Otsuka
Toshiyuki
T
Yamazaki
Yuichi
Y
Kosone
Takashi
T
Sohara
Naondo
N
Ichikawa
Takeshi
T
Sato
Ken
K
Kakizaki
Satoru
S
Takagi
Hitoshi
H
Mori
Masatomo
M
D000199:Actins / Q000378:metabolism; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001663:Bilirubin / Q000097:blood; D015153:Blotting, Western; D002251:Carbon Tetrachloride / Q000633:toxicity*; D005786:Gene Expression Regulation / Q000187:drug effects*; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000378:metabolism*; D008103:Liver Cirrhosis / Q000139:chemically induced* / Q000378:metabolism; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic / Q000235:genetics; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
D000199:Actins; D053773:Transforming Growth Factor beta1; D017228:Hepatocyte Growth Factor; D002251:Carbon Tetrachloride; D000410:Alanine Transaminase; D053509:Matrix Metalloproteinase 13; D001663:Bilirubin