Role of ERK1/2 and p38 mitogen-activated protein kinases in the regulation of thrombospondin-1 by TGF-β1 in rat proximal tubular cells and mouse fibroblasts
Role of ERK1/2 and p38 mitogen-activated protein kinases in the regulation of thrombospondin-1 by TGF-β1 in rat proximal tubular cells and mouse fibroblasts
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DOI：
10.1681/asn.2004080689
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发表时间：
2005-04-01
影响因子：
13.6
通讯作者：
Sautin, YY
中科院分区：
文献类型：
--
作者：
Nakagawa, T;Lan, HY;Sautin, YY
血小板反应蛋白-1（TSP-1）抑制血管生成并激活潜伏的TGF-β 1，这两者都与肾脏疾病的进展密切相关。最近，据报道，在大鼠肾小管上皮细胞以及小鼠成纤维细胞中，Smad 2而不是Smad 3响应于TGF-β 1调节TSP-1的表达。本研究探讨了ERK 1/2和p38丝裂原活化蛋白激酶（MAPK）的作用。TGF-β 1在大鼠近端肾小管细胞系NRK 52 E中激活ERK 1/2和p38。阻断ERK 1/2和p38可抑制TGF-β 1诱导的TSP-1 mRNA和蛋白表达。接下来，检查Smad 2与ERK 1/2或p38之间的串扰。阻断ERK 1/2或p38不能抑制TGF-β 1诱导的Smad 2活化，而Smad 7过表达抑制Smad 2抑制ERK 1/2的磷酸化，但不能抑制p38对TGF-β 1的反应。使用来自Smad 2敲除胚胎的小鼠成纤维细胞观察到类似的结果，因为TGF-β 1能够激活该细胞系中的p38而不是ERK 1/2。总之，TSP-1的表达在大鼠近端肾小管细胞和小鼠成纤维细胞中受ERK 1/2和p38 MAPK的调节，以响应TGF-β 1。ERK 1/2的激活依赖于Smad 2的激活，而p38的激活不依赖于Smad 2。由于TSP-1是一种主要的抗血管生成分子和TGF-β 1的激活剂，这为TGF-β 1介导间质纤维化和进行性肾病的机制提供了重要的见解。
Thrombospondin-1 (TSP-1) inhibits angiogenesis and activates latent TGF-beta 1, both of which are strongly associated with progression of renal disease. Recently, it was reported that Smad2 but not Smad3 regulates TSP-1 expression in response to TGF-beta 1 in rat tubular epithelial cells as well as in mouse fibroblasts. This study investigated the role of ERK1/2 and p38 mitogen-activated protein kinases (MAPK). TGF-beta 1 activated both ERK1/2 and p38 in the rat proximal tubular cell line NRK52E. Blocking ERK1/2 and p38 inhibited TGF-beta 1-induced TSP-1 mRNA and protein expression. Next, the cross-talk between Smad2 and ERK1/2 or p38 was examined. Whereas blocking of ERK1/2 or p38 failed to inhibit TGF-beta 1-induced Smad2 activation, inhibition of Smad2 by Smad7 overexpression inhibited the phosphorylation of ERK1/2 but not p38 in response to TGF-beta 1. Similar results were observed using mouse fibroblasts from Smad2 knockout embryos, in that TGF-beta 1 was able to activate p38 but not ERK1/2 in this cell line. In conclusion, TSP-1 expression is regulated by both ERK1/2 and p38 MAPK in rat proximal tubular cells and mouse fibroblasts in response to TGF-beta 1. The ERK1/2 activation is dependent on Smad2 activation, whereas the p38 activation occurs independent of Smad2. Because TSP-1 is a major antiangiogenic molecule and an activator of TGF-beta 1, this provides an important insight to the mechanism by which TGF-beta 1 may mediate interstitial fibrosis and progressive renal disease.