Tissue-type plasminogen activator promotes murine myofibroblast activation throught LDL receptor-related protein 1-mediated integrin signaling
Tissue-type plasminogen activator promotes murine myofibroblast activation throught LDL receptor-related protein 1-mediated integrin signaling
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DOI：
10.1172/jci32301
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发表时间：
2007-12-01
影响因子：
15.9
通讯作者：
Liu, Youhua
中科院分区：
文献类型：
--
作者：
Hu, Kebin;Wu, Chuanyue;Liu, Youhua
间质成纤维细胞活化成为α-SMA阳性肌成纤维细胞是慢性肾纤维化演变的重要步骤，因为肌成纤维细胞负责ECM组分的产生和沉积，ECM组分是该疾病的标志。在这里，我们描述了一个信号通路，导致这种激活。组织型纤溶酶原激活剂（tPA）促进TGF-β 1介导的大鼠肾间质成纤维细胞α-SMA和I型胶原的表达。这种纤维化作用不依赖于其蛋白酶活性，但需要其膜受体LDL受体相关蛋白1（LRP-1）。在大鼠肾成纤维细胞中，tPA诱导快速LRP-1酪氨酸磷酸化，并通过促进LRP-1/β 1整联蛋白复合物的形成增强β 1整联蛋白募集。阻断或敲低β 1整合素可消除I型胶原和α-SMA表达。此外，抑制整合素连接激酶（ILK），β 1整合素的下游效应子，或破坏β 1整合素/ILK接合，废除tpA作用，而ILK的异位表达模拟tPA促进肌成纤维细胞活化。在梗阻性损伤后的小鼠肾髓质中，tPA和α-SMA与LRP-1共定位，并且tPA缺乏减少LRP-1/β 1整合素相互作用和肌成纤维细胞活化。这些发现表明，tpA诱导LRP-1酪氨酸磷酸化，这反过来又促进LRP-1介导的β 1整联蛋白和下游ILK信号传导的募集，从而导致肌成纤维细胞活化。这项研究表明tPA是一种促进肾纤维化进展的纤维化细胞因子。
The activation of interstitial fibroblasts to become alpha-SMA-positive myofibroblasts is an essential step in the evolution of chronic kidney fibrosis, as myofibroblasts are responsible for the production and deposition of the ECM components that are a hallmark of the disease. Here we describe a signaling pathway that leads to this activation. Tissue-type plasminogen activator (tPA) promoted TGF-beta 1-mediated alpha-SMA and type I collagen expression in rat kidney interstitial fibroblasts. This fibrogenic effect was independent of its protease activity but required its membrane receptor, the LDL receptor-related protein 1 (LRP-1). In rat kidney fibroblasts, tPA induced rapid LRP-1 tyrosine phosphorylation and enhanced P I integrin recruitment by facilitating the LRP-1/beta 1 integrin complex formation. Blockade or knockdown of beta 1 integrin abolished type I collagen and a-SMA expression. Furthermore, inhibition of the integrin-linked kinase (ILK), a downstream effector of beta 1 integrin, or disruption of beta 1 integrin/ILK engagement, abrogated the tpA action, whereas ectopic expression of ILK mimicked tPA in promoting myofibroblast activation. In murine renal interstitium after obstructive injury, tPA and alpha-SMA colocalized with LRP-1, and tPA deficiency reduced LRP-1/beta 1 integrin interaction and myofibroblast activation. These findings show that tpA induces LRP-1 tyrosine phosphorylation, which in turn facilitates the LRP-1-mediated recruitment of beta 1 integrin and downstream ILK signaling, thereby leading to myofibroblast activation. This study implicates tPA as a fibrogenic cytokine that promotes the progression of kidney fibrosis.