Angiotensin-II type 1 receptor-mediated Janus kinase 2 activation induces liver fibrosis.
Angiotensin-II type 1 receptor-mediated Janus kinase 2 activation induces liver fibrosis.
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DOI：
10.1002/hep.27117
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发表时间：
2014-07
期刊：
影响因子：
--
通讯作者：
Trebicka J
中科院分区：
文献类型：
--
作者：
Granzow M;Schierwagen R;Klein S;Kowallick B;Huss S;Linhart M;Mazar IG;Görtzen J;Vogt A;Schildberg FA;Gonzalez-Carmona MA;Wojtalla A;Krämer B;Nattermann J;Siegmund SV;Werner N;Fürst DO;Laleman W;Knolle P;Shah VH;Sauerbruch T;Trebicka J
肾素血管紧张素系统的激活，导致血管紧张素 II（AngII）1 型受体（AT1R）受到刺激，这是肝纤维化发展的一个重要因素。在此，我们探究了Janus激酶2（JAK2）作为AT1R一种新发现的细胞内效应因子在介导肝纤维化过程中的作用。将来自啮齿动物和人类的纤维化肝脏样本与各自的对照样本进行比较。通过实时聚合酶链反应、蛋白质免疫印迹、免疫组织化学和共聚焦显微镜分析JAK2及下游效应因子的转录、蛋白表达、激活情况和定位。通过胆管结扎（BDL）、四氯化碳中毒、硫代乙酰胺中毒或持续输注血管紧张素 II 诱导实验性肝纤维化。使用AG490抑制JAK2。体外实验采用原代啮齿动物肝星状细胞（HSCs）、库普弗细胞（KCs）和肝细胞，以及原代人源细胞和人源LX2细胞进行。
在实验性啮齿动物和人类肝纤维化中，JAK2的表达和活性增加，特别是在肌成纤维细胞样的肝星状细胞中。在野生型动物中，AT1R的刺激通过JAK2的磷酸化以及随后RhoA/Rho激酶的激活，在体内导致肝星状细胞的活化和纤维化。这些效应在AT1R基因敲除小鼠中未出现。在啮齿动物肝纤维化模型中，JAK2的药物抑制减轻了肝纤维化。在体外，与从啮齿动物分离的静止肝星状细胞、库普弗细胞和肝细胞相比，活化的肝星状细胞中JAK2及下游效应因子的表达和激活增加。在原代人源细胞和LX2细胞中，AG490阻断了血管紧张素 II 诱导的促纤维化基因表达。JAK2的过表达导致LX2细胞中促纤维化基因表达增加，而这一现象被AG490阻断。
我们的研究证实了JAK2在肝星状细胞中对肝纤维化发展具有重要的细胞内在作用。因此，抑制JAK2可能为肝纤维化提供一种有前景的治疗方法。
Activation of the renin angiotensin system resulting in stimulation of angiotensin-II (AngII) type I receptor (AT1R) is an important factor in the development of liver fibrosis. Here, we investigated the role of Janus kinase 2 (JAK2) as a newly described intra-cellular effector of AT1R in mediating liver fibrosis. Fibrotic liver samples from rodents and humans were compared to respective controls. Transcription, protein expression, activation, and localization of JAK2 and downstream effectors were analyzed by realtime polymerase chain reaction, western blotting, immunohistochemistry, and confocal microscopy. Experimental fibrosis was induced by bile duct ligation (BDL), CCl4 intoxication, thioacetamide intoxication or continuous AngII infusion. JAK2 was inhibited by AG490. In vitro experiments were performed with primary rodent hepatic stellate cells (HSCs), Kupffer cells (KCs), and hepatocytes as well as primary human and human-derived LX2 cells. JAK2 expression and activity were increased in experimental rodent and human liver fibrosis, specifically in myofibroblastic HSCs. AT1R stimulation in wild-type animals led to activation of HSCs and fibrosis in vivo through phosphorylation of JAK2 and subsequent RhoA/Rho-kinase activation. These effects were prevented in AT1R–/– mice. Pharmacological inhibition of JAK2 attenuated liver fibrosis in rodent fibrosis models. In vitro, JAK2 and downstream effectors showed increased expression and activation in activated HSCs, when compared to quiescent HSCs, KCs, and hepatocytes isolated from rodents. In primary human and LX2 cells, AG490 blocked AngII-induced profibrotic gene expression. Overexpression of JAK2 led to increased profibrotic gene expression in LX2 cells, which was blocked by AG490. Our study substantiates the important cell-intrinsic role of JAK2 in HSCs for development of liver fibrosis. Inhibition of JAK2 might therefore offer a promising therapy for liver fibrosis.
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