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学科主题: 基础医学
题名:
Kindlin-2 regulates renal tubular cell plasticity by activation of Ras and its downstream signaling
作者: Wei, Xiaofan1,2,3; Wang, Xiang1,2,3; Xia, Yang1,2,3; Tang, Yan1,2,3; Li, Feng1,2,3; Fang, Weigang1,4; Zhang, Hongquan1,2,3
关键词: tubular cell plasticity ; kindlin-2 ; Ras signaling
刊名: AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY
发表日期: 2014
DOI: 10.1152/ajprenal.00499.2013
卷: 306, 期:2, 页:F271-F278
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology
类目[WOS]: Physiology ; Urology & Nephrology
研究领域[WOS]: Physiology ; Urology & Nephrology
关键词[WOS]: EPITHELIAL-MESENCHYMAL TRANSITION ; UNILATERAL URETERAL OBSTRUCTION ; NUCLEOTIDE EXCHANGE FACTOR ; GROWTH-FACTOR-BETA ; INTERSTITIAL FIBROSIS ; EGF RECEPTOR ; CANCER CELLS ; EMT ; MECHANISMS ; KINASE
英文摘要:

Kindlin-2 is an adaptor protein that contributes to renal tubulointerstitial fibrosis (TIF). Epithelial-to-mesenchymal transition (EMT) in tubular epithelial cells was regarded as one of the key events in TIF. To determine whether kindlin-2 is involved in the EMT process, we investigated its regulation of EMT in human kidney tubular epithelial cells (TECs) and explored the underlying mechanism. In this study, we found that overexpression of kindlin-2 suppressed epithelial marker E-cadherin and increased the expression of fibronectin and the myofibroblast marker alpha-smooth muscle actin (SMA). Kindlin-2 significantly activated ERK1/2 and Akt, and inhibition of ERK1/2 or Akt reversed kindlin-2-induced EMT in human kidney TECs. Mechanistically, kindlin-2 interacted with Ras and son of sevenless (Sos)-1. Furthermore, overexpression of kindlin-2 increased Ras activation through recruiting Sos-1. Treatment with a Ras inhibitor markedly repressed kindlin-2-induced ERK1/2 and Akt activation, leading to restraint of EMT. We further demonstrated that knockdown of kindlin-2 inhibited EGF-induced Ras-Sos-1 interaction, resulting in reduction of Ras activation and suppression of EMT stimulated by EGF. Importantly, we found that depletion of kindlin-2 significantly inhibited activation of ERK1/2 and Akt signaling in mice with unilateral ureteral obstruction. We conclude that kindlin-2, through activating Ras and the downstream ERK1/2 and Akt signaling pathways, plays an important role in regulating renal tubular EMT and could be a potential therapeutic target for the treatment of fibrotic kidney diseases.

语种: 英语
所属项目编号: 2013CB910501 ; 2010CB912203 ; 2010CB529402 ; 30830048 ; 81230051 ; 31170711 ; 81300563 ; 7120002 ; BMU20120314 ; BMU20130364 ; 2013M540028
项目资助者: Ministry of Science and Technology of China ; National Natural Science Foundation of China ; 111 Project of the Ministry of Education ; Beijing Natural Science Foundation ; Peking University ; Leading Academic Discipline Project of the Beijing Education Bureau ; China Postdoctoral Science Foundation ; Peking-Tsinghua Center for Life Sciences
WOS记录号: WOS:000329860000014
Citation statistics:
内容类型: 期刊论文
版本: 出版稿
URI标识: http://ir.bjmu.edu.cn/handle/400002259/61714
Appears in Collections:基础医学院_病理学系_期刊论文

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作者单位: 1.Peking Univ, Hlth Sci Ctr, Minist Educ, Key Lab Carcinogenesis & Translat Res, Beijing 100191, Peoples R China
2.Peking Univ, Hlth Sci Ctr, State Key Lab Nat & Biomimet Drugs, Beijing 100191, Peoples R China
3.Peking Univ, Hlth Sci Ctr, Dept Anat Histol & Embryol, Lab Mol Cell Biol & Tumor Biol, Beijing 100191, Peoples R China
4.Peking Univ, Hlth Sci Ctr, Dept Pathol, Beijing 100191, Peoples R China

Recommended Citation:
Wei, Xiaofan,Wang, Xiang,Xia, Yang,et al. Kindlin-2 regulates renal tubular cell plasticity by activation of Ras and its downstream signaling[J]. AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY,2014,306(2):F271-F278.
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