Cdc42-interacting protein-4 promotes TGF-Β1-induced epithelial-mesenchymal transition and extracellular matrix deposition in renal proximal tubular epithelial cells.
Cdc42-interacting protein-4 promotes TGF-Β1-induced epithelial-mesenchymal transition and extracellular matrix deposition in renal proximal tubular epithelial cells.
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DOI：
10.7150/ijbs.3490
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发表时间：
2012
影响因子：
9.2
通讯作者：
Xu G
中科院分区：
文献类型：
--
作者：
Bai S;Zeng R;Zhou Q;Liao W;Zhang Y;Xu C;Han M;Pei G;Liu L;Liu X;Yao Y;Xu G
Cdc42相互作用蛋白4（CIP4）是F-BAR（Fer/CIP4和Bin、两性蛋白、Rvs）家族成员，调节膜变形和内吞作用，在癌细胞的细胞外基质（ECM）沉积和侵袭中发挥关键作用。这些过程类似于肾小管上皮细胞初始上皮间质转化（EMT）期间观察到的过程。在本研究过程中，研究了 CIP4 在肾小管 EMT 和肾小管间质纤维化中的作用，结果表明 5/6 肾切除大鼠和 TGF-β1 处理的 HK-2 细胞的肾小管上皮细胞中 CIP4 的表达增加。内源性 CIP4 在整个细胞质中呈现点状定位，在 HK-2 细胞的核周区域观察到水平升高。 TGF-β1处理后，CIP4表达增加，在细胞外周形成簇，并逐渐重新分布到细胞质中。同时，细胞中 EMT 的诱导通过形态学变化、E-钙粘蛋白缺失、α-SMA 表达增加和纤连蛋白分泌的普遍发生得到证实。 CIP4 的过度表达促进了与 EMT 中常见的特征相似的特征，并且能够敲低 CIP4 的小干扰 RNA (siRNA) 分子被用来证明逆转的 EMT。总的来说，目前的研究结果表明，CIP4 促进肾小管上皮细胞中 TGF-β1 诱导的 EMT。通过这种机制，CIP4能够诱导ECM沉积并加剧慢性肾衰竭的进行性纤维化。
Cdc42-interacting protein-4 (CIP4) is an F-BAR (Fer/CIP4 and Bin, amphiphysin, Rvs) family member that regulates membrane deformation and endocytosis, playing a key role in extracellular matrix (ECM) deposition and invasion of cancer cells. These processes are analogous to those observed during the initial epithelial-mesenchymal transition (EMT) of renal tubular epithelial cells. The role of CIP4 in renal tubular EMT and renal tubulointerstitial fibrosis was investigated over the course of the current study, demonstrating that the expression of CIP4 increased in the tubular epithelia of 5/6-nephrectomized rats and TGF-β1 treated HK-2 cells. Endogenous CIP4 evidenced punctate localization throughout the cytosol, with elevated levels observed in the perinuclear region of HK-2 cells. Subsequent to TGF-β1 treatment, CIP4 expression increased, forming clusters at the cell periphery that gradually redistributed into the cytoplasm. Simultaneously, EMT induction in cells was confirmed by the prevalence of morphological changes, loss of E-cadherin, increase in α-SMA expression, and secretion of fibronectin. Overexpression of CIP4 promoted characteristics similar to those commonly observed in EMT, and small interfering RNA (siRNA) molecules capable of CIP4 knockdown were used to demonstrate reversed EMT. Cumulatively, results of the current study suggest that CIP4 promotes TGF-β1-induced EMT in tubular epithelial cells. Through this mechanism, CIP4 is capable of inducing ECM deposition and exacerbating progressive fibrosis in chronic renal failure.
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