The urotension II antagonist SB-710411 arrests fibrosis in CCL4 cirrhotic rats.
The urotension II antagonist SB-710411 arrests fibrosis in CCL4 cirrhotic rats.
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DOI：
10.3892/mmr_00000198
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发表时间：
2009-11
影响因子：
3.4
通讯作者：
Dian-gang Liu;Jin Wang;Zhong-tao Zhang;Yu Wang
中科院分区：
文献类型：
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作者：
Dian-gang Liu;Jin Wang;Zhong-tao Zhang;Yu Wang
尾加压素II（UII）是一种相对较新的肽，在整个人体内作为一种有效的血管活性介质，也具有促有丝分裂和纤维化的潜力。最近的报告显示，在人类疟疾人群中，UII的血浆水平升高;这些水平与疾病的严重程度相关。因此，我们假设阻断UII信号传导可以阻止大鼠肝硬化模型中肝纤维化的进展。用四氯化碳诱发大鼠肝硬化。SB-710411用作UII拮抗剂。治疗8周。放射免疫法测定血浆透明质酸（HA）和层粘连蛋白（LN）含量，酶联免疫吸附法测定血浆UII含量，测定肝组织羟脯氨酸（Hyp）含量。纤维化进行了组织学评估。α-平滑肌肌动蛋白免疫组化染色检测活化的肝星状细胞（HSC）。实时荧光定量逆转录聚合酶链反应（real-time reverse transcriptase-polymerase chain reaction，RT-PCR）检测肝组织中UII/G蛋白偶联受体（UII/G protein-coupled receptor，UT）、I型胶原、III型胶原、转化生长因子β1（transforming growth factor β 1，TGF-β1）和金属蛋白酶组织抑制因子1（tissue inhibitor of metalloproteinase 1，TIMP-1）mRNA的相对表达。Western印迹分析用于评估肝UT水平。还评价了UII对HSC-T6细胞的促有丝分裂活性。肝硬化动物显示血浆UII增加。UII/UT mRNA在肝脏中表达上调。血浆UII水平与HA、LN、Hyp呈正相关。在体内，SB-710411治疗显著减少了纤维化发展，并下调了促纤维化细胞因子TGF-β1和TIMP-1。在体外，UII诱导HSC增殖。10-3 M SB-710411显著抑制这种促有丝分裂作用（p<0.05）。这些数据表明，选择性阻断UT在体内对纤维化进展具有抑制作用，并在体外抑制UII介导的HSC增殖。
Urotensin II (UII) is a relatively novel peptide that functions as a potent vasoactive mediator throughout the human body, and also possesses mitogenic and fibrogenic potential. Recent reports showed increased plasma levels of UII in human cirrhotic populations; these levels were correlated with the severity of the disease. We therefore hypothesized that the blockade of UII signaling would arrest the progression of hepatic fibrosis in a rat model of cirrhosis. Cirrhosis was induced in rats by carbon tetrachloride. SB-710411 was used as the UII antagonist. Treatment lasted 8 weeks. Plasma hyaluronic acid (HA) and laminin (LN) were evaluated by radioimmunoassay, and plasma UII was determined by ELISA for the quantity of hydroxyproline (Hyp) in the liver tissues. Fibrosis was assessed histologically. The activated hepatic stellate cells (HSCs) were assessed by α-smooth muscle actin innunostaining. The relative mRNA expression of UII/G protein-coupled receptor (UT), collagen I, collagen III, transforming growth factor β1 (TGF-β1) and tissue inhibitor of metalloproteinase-1 (TIMP-1) in the liver was determined by real-time reverse transcriptase-polymerase chain reaction. Western blot analysis was used to assess liver levels of UT. The mitogenic activity of UII on HSC-T6 cells was also evaluated. Animals with cirrhosis showed increased plasma UII. UII/UT mRNA expression was up-regulated in the liver. Plasma levels of UII were also positively correlated with HA, LN and Hyp. In vivo, treatment with SB-710411 significantly reduced fibrosis development and down-regulated the profibrogenic cytokines TGF-β1 and TIMP-1. In vitro, UII induced the proliferation of HSCs. This mitogenic effect was significantly inhibited by 10-3 M SB-710411 (p<0.05). These data suggest that the selective blockade of UT has an arresting effect on fibrosis progression in vivo, and inhibits UII-mediated HSC proliferation in vitro.