Angiotensin II Induces Epithelial-to-Mesenchymal Transition in Renal Epithelial Cells through Reactive Oxygen Species/Src/Caveolin-Mediated Activation of an Epidermal Growth Factor Receptor-Extracellular Signal-Regulated Kinase Signaling Pathway
Angiotensin II Induces Epithelial-to-Mesenchymal Transition in Renal Epithelial Cells through Reactive Oxygen Species/Src/Caveolin-Mediated Activation of an Epidermal Growth Factor Receptor-Extracellular Signal-Regulated Kinase Signaling Pathway
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DOI：
10.1128/mcb.06410-11
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发表时间：
2012-03-01
影响因子：
5.3
通讯作者：
Harris, Raymond C.
中科院分区：
文献类型：
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作者：
Chen, Jianchun;Chen, Jian-Kang;Harris, Raymond C.
慢性激活的肾素-血管紧张素系统在进行性肾损伤中起有害作用，并且已知肾近端小管在肾小管间质纤维化中起重要作用;然而，潜在的分子机制尚不清楚。在这里，我们报告，在近端小管样LLCPKcl 4细胞表达血管紧张素II（Ang II）1型受体，Ang II诱导的细胞形态和上皮间质转化（EMT）标志物的表达的变化，这是由促分裂素活化蛋白（MAP）激酶/细胞外信号调节激酶（ERK）激活激酶（MEK）抑制剂PD 98059或Src激酶抑制剂PP 2抑制。血管紧张素II刺激磷酸化的小窝蛋白-1（Cav）在Y14和表皮生长因子受体（EGFR）在Y845和诱导协会的这些磷蛋白在小窝蛋白丰富的脂筏，从而导致延长EGFR-ERK信号被抑制的Nox 4小干扰RNA（siRNA）和Src siRNA。两种不同的抗氧化剂不仅抑制Y 416处Src的磷酸化，而且还阻断EGFR-ERK信号传导。此外，厄洛替尼（EGFR酪氨酸激酶抑制剂）、EGFR siRNA和Cav siRNA均抑制Ang II诱导的延长的EGFR-ERK信号传导和表型变化。因此，本报告首次提供了活性氧（ROS）/Src依赖的持续Cav-EGFR-ERK信号转导激活介导肾小管细胞去分化的证据，并确定了一种新的分子机制，可能参与慢性暴露于Ang II引起的进行性肾损伤
Chronic activation of the renin-angiotensin system plays a deleterious role in progressive kidney damage, and the renal proximal tubule is known to play an important role in tubulointerstitial fibrosis; however, the underlying molecular mechanism is unclear. Here we report that in the proximal tubule-like LLCPKcl4 cells expressing angiotensin II (Ang II) type 1 receptor, Ang II induced changes in cell morphology and expression of epithelial-to-mesenchymal transition (EMT) markers, which were inhibited by the miotogen-activated protein (MAP) kinase/extracellular signal-regulated kinase (ERK)-activating kinase (MEK) inhibitor PD98059 or the Src kinase inhibitor PP2. Ang II-stimulated phosphorylation of caveolin-1 (Cav) at Y14 and epidermal growth factor receptor (EGFR) at Y845 and induced association of these phosphoproteins in caveolin-enriched lipid rafts, thereby leading to prolonged EGFR-ERK signaling that was inhibited by Nox4 small interfering RNA (siRNA) and Src siRNA. Two different antioxidants not only inhibited phosphorylation of Src at Y416 but also blocked the EGFR-ERK signaling. Moreover, erlotinib (the EGFR tyrosine kinase inhibitor), EGFR siRNA, and Cav siRNA all inhibited both prolonged EGFR-ERK signaling and phenotypic changes induced by Ang II. Thus, this report provides the first evidence that reactive oxygen species (ROS)/Src-dependent activation of persistent Cav-EGFR-ERK signaling mediates renal tubular cell dedifferentiation and identifies a novel molecular mechanism that may be involved in progressive renal injury caused by chronic exposure to Ang II