tPA Is a Potent Mitogen for Renal Interstitial Fibroblasts Role of β1 Integrin/Focal Adhesion Kinase Signaling
tPA Is a Potent Mitogen for Renal Interstitial Fibroblasts Role of β1 Integrin/Focal Adhesion Kinase Signaling
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DOI：
10.2353/ajpath.2010.091269
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发表时间：
2010-09-01
影响因子：
6
通讯作者：
Liu, Youhua
中科院分区：
文献类型：
--
作者：
Hao, Sha;Shen, Hongmei;Liu, Youhua
间质成纤维细胞的增殖和扩张是进行性慢性肾脏疾病的主要特征。然而，间质成纤维细胞增殖如何控制仍然不明确。在这里，我们表明，组织型纤溶酶原激活剂（tPA）是一种有效的有丝分裂原，促进间质成纤维细胞增殖，通过级联信号事件。在体外，tPA促进大鼠肾成纤维细胞（NRK-49 F）的细胞增殖，通过细胞计数，细胞增殖试验，和溴脱氧尿苷标记评估。tPA还促进NRK-49 F细胞周期进程。tPA诱导的成纤维细胞增殖与许多增殖相关基因的表达增加相关，包括c-fos、c-myc、增殖细胞核抗原和细胞周期蛋白D1。tPA的促有丝分裂作用不依赖于其蛋白酶活性，但需要LDL受体相关蛋白1。有趣的是，β 1整联蛋白信号的抑制阻止了tPA介导的成纤维细胞增殖。tPA迅速诱导粘着斑激酶（FAK）的酪氨酸磷酸化，这导致其下游促分裂原活化蛋白激酶信号传导的激活。阻断FAK，而不是整合素连接的激酶，取消了tPA触发的细胞外信号调节蛋白激酶1/2激活，增殖相关基因诱导和成纤维细胞增殖。在体内，与野生型对照组相比，阻塞性损伤后tPA基因敲除小鼠间质肌成纤维细胞的增殖减弱。这些研究表明，tPA是一种有效的有丝分裂原，通过LDL受体相关蛋白1介导的β 1整合素和FAK信号传导促进肾间质成纤维细胞增殖。(Am J Pathol 2010，177：1164-1175，DOI：10.2353/ajpath.2010.091269）
Proliferation and expansion of interstitial fibroblasts are predominant features of progressive chronic kidney diseases. However, how interstitial fibroblast proliferation is controlled remains ambiguous. Here we show that tissue-type plasminogen activator (tPA) is a potent mitogen that promotes interstitial fibroblast proliferation through a cascade of signaling events. In vitro, tPA promoted cell proliferation of rat kidney fibroblasts (NRK-49F), as assessed by cell counting, cell proliferation assay, and bromodeoxyuridine labeling. tPA also accelerated NRK-49F cell cycle progression. Fibroblast proliferation induced by tPA was associated with an increased expression of numerous proliferation-related genes, including c-fos, c-myc, proliferating cell nuclear antigen, and cyclin D1. The mitogenic effect of tPA was independent of its protease activity, but required LDL receptor-related protein 1. Interestingly, inhibition of beta 1 integrin signaling prevented tPA-mediated fibroblast proliferation. tPA rapidly induced tyrosine phosphorylation of focal adhesion kinase (FAK), which led to activation of its downstream mitogen-activated protein kinase signaling. Blockade of FAK, but not integrin-linked kinase, abolished the tPA-triggered extracellular signal-regulated protein kinase 1/2 activation, proliferation-related gene induction, and fibroblast proliferation. In vivo, proliferation of interstitial myofibroblasts in tPA null mice was attenuated after obstructive injury, compared with the wild-type controls. These studies illustrate that tPA is a potent mitogen that promotes renal interstitial fibroblast proliferation through LDL receptor-related protein 1-mediated beta 1 integrin and FAK signaling. (Am J Pathol 2010, 177:1164-1175, DOI: 10.2353/ajpath.2010.091269)