Overexpression of NK2 promotes liver fibrosis in carbon tetrachloride-induced chronic liver injury
Overexpression of NK2 promotes liver fibrosis in carbon tetrachloride-induced chronic liver injury
复制标题
DOI：
10.1111/j.1478-3231.2007.01616.x
复制
发表时间：
2008-01-01
影响因子：
6.7
通讯作者：
Mori, Masatomo
中科院分区：
文献类型：
--
作者：
Hagiwara, Satoshi;Otsuka, Toshiyuki;Mori, Masatomo
背景/目的：肝细胞生长因子（HGF）可抑制动物模型中四氯化碳（CCl4）诱导的肝纤维化。 NK2是HGF的天然剪接变体，但其体内功能仍有待阐明。我们研究了 NK2 对 CCl4 诱导的肝纤维化的体内影响。方法：NK2转基因小鼠和野生型（WT）小鼠每周腹腔注射CCl4两次。通过Azan-Mallory染色评估肝纤维化的程度。通过实时聚合酶链式反应检测转化生长因子-β 1 (TGF-β 1) 和基质金属蛋白酶-13 (MMP-13) mRNA 的表达水平。通过蛋白质印迹分析测定α-平滑肌肌动蛋白（α-SMA）、c-Met 及其磷酸化的蛋白水平。结果：NK2转基因小鼠的肝纤维化明显比WT小鼠更严重。与WT小鼠相比，CCl4给药增加了NK2转基因小鼠肝脏中TGF-β1 mRNA和α-SMA蛋白的表达水平，并降低了MMP-13 mRNA的表达。肝脏中c-Met蛋白的表达与纤维化程度相一致。至于 c-Met 激活，NK2 和 WT 肝脏之间没有发现差异。结论：NK2过表达在CCl4诱导的慢性肝损伤中作为HGF的拮抗剂并促进肝纤维化。
Background/Aims: 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-beta 1 (TGF-beta 1) 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-beta 1 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. Conclusion: Overexpression of NK2 acts as an antagonist of HGF and promotes liver fibrosis in CCl4-induced chronic liver injury.