Suppression of PAI-1 Expression Through Inhibition of the EGFR-Mediated Signaling Cascade in Rat Kidney Fibroblast by Ascofuranone
Suppression of PAI-1 Expression Through Inhibition of the EGFR-Mediated Signaling Cascade in Rat Kidney Fibroblast by Ascofuranone
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DOI：
10.1002/jcb.22130
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发表时间：
2009-05-15
影响因子：
4
通讯作者：
Chang, Young-Chae
中科院分区：
文献类型：
--
作者：
Cho, Hyun-Ji;Kang, Jeong-Han;Chang, Young-Chae
肾小球硬化中的纤维化会导致肾功能的进行性丧失。转化生长因子-β是一种主要的促纤维化细胞因子，可诱导纤溶酶原激活物抑制物-1的合成，而纤溶酶原激活物抑制物-1在纤维化的发生发展中起着至关重要的作用。在这里，我们发现一种异戊二烯类抗生素，阿斯可呋喃酮，可以抑制由转化生长因子-β诱导的肾成纤维细胞中促纤维化因子的表达，包括基质蛋白和PAI-1。阿斯可呋喃酮选择性地抑制表皮生长因子受体(EGFR)的磷酸化及其下游的Raf-1、MEK-1/2和ERK-1/2。PAI-1的转录也被MEK-1/2或EGFR的激酶抑制剂和干扰EGFR的小RNA所抑制。阿司可呋喃酮抑制细胞金属蛋白酶活性，金属蛋白酶抑制剂抑制EGFR磷酸化和PAI-1转录。这些结果表明，阿司可呋喃酮通过抑制金属蛋白酶激活的EGFR依赖的信号转导途径来抑制促纤维化因子的表达。J.细胞。生物化学。107：335-344,2009。(C)2009年Wiley-Liss，Inc.
Fibrosis in glomerulosclerosis causes progressive loss of renal function. Transforming growth factor (TGF)-beta, one of the major profibrotic cytokines, induces the synthesis of plasminogen activator inhibitor (PAI)-1, a factor that plays a crucial role in the development of fibrosis. Here, we found that an isoprenoid antibiotic, ascofuranone, suppresses expression of profibrotic factors including matrix proteins and PAI-1 induced by TGF-beta in renal fibroblasts. Ascofuranone selectively inhibits phosphorylation of epidermal growth factor receptor (EGFR), and downstream kinases such as Raf-1, MEK-1/2, and ERK-1/2. PAI-1 transcription also is suppressed by treatment with kinase inhibitors for MEK-1/2 or EGFR, and with small interfering RNA for EGFR. Ascofuranone inhibits cellular metalloproteinase activity, and an inhibitor of metalloproteinases suppresses EGFR phosphorylation and PAI-1 transcription. These results suggest that ascofuranone suppresses expression of profibrotic factors through the inhibition of an EGFR-dependent signal transduction pathway activated by metalloproteinases. J. Cell. Biochem. 107: 335-344, 2009. (C) 2009 Wiley-Liss, Inc.