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Role for integrin-linked kinase in mediating tubular epithelial to mesenchymal transition and renal interstitial fibrogenesis
Yingjian Li, … , Chuanyue Wu, Youhua Liu
Yingjian Li, … , Chuanyue Wu, Youhua Liu
Published August 15, 2003
Citation Information: J Clin Invest. 2003;112(4):503-516. https://doi.org/10.1172/JCI17913.
View: Text | PDF | Corrigendum
Article Nephrology

Role for integrin-linked kinase in mediating tubular epithelial to mesenchymal transition and renal interstitial fibrogenesis

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Abstract

Under pathologic conditions, renal tubular epithelial cells can undergo epithelial to mesenchymal transition (EMT), a phenotypic conversion that is believed to play a critical role in renal interstitial fibrogenesis. However, the underlying mechanism that governs this process remains largely unknown. Here we demonstrate that integrin-linked kinase (ILK) plays an important role in mediating tubular EMT induced by TGF-β1. TGF-β1 induced ILK expression in renal tubular epithelial cells in a time- and dose-dependent manner, which was dependent on intracellular Smad signaling. Forced expression of ILK in human kidney proximal tubular epithelial cells suppressed E-cadherin expression and induced fibronectin expression and its extracellular assembly. ILK also induced MMP-2 expression and promoted cell migration and invasion in Matrigel. Conversely, ectopic expression of a dominant-negative, kinase-dead form of ILK largely abrogated TGF-β1–initiated tubular cell phenotypic conversion. In vivo, ILK was markedly induced in renal tubular epithelia in mouse models of chronic renal diseases, and such induction was spatially and temporally correlated with tubular EMT. Moreover, inhibition of ILK expression by HGF was associated with blockade of tubular EMT and attenuation of renal fibrosis. These findings suggest that ILK is a critical mediator for tubular EMT and likely plays a crucial role in the pathogenesis of chronic renal fibrosis.

Authors

Yingjian Li, Junwei Yang, Chunsun Dai, Chuanyue Wu, Youhua Liu

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Figure 9

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Induction of ILK expression in renal epithelia in diabetic nephropathy i...
Induction of ILK expression in renal epithelia in diabetic nephropathy is associated with tubular EMT. (a and b) Western blot analysis shows induction of ILK expression in diabetic nephropathy in mice. Whole-tissue homogenates derived from control or diabetic mice were immunoblotted with Ab’s against ILK and actin, respectively. The relative abundance of ILK (fold induction) is presented in b after normalization with actin. *P < 0.05 (n = 3). (c–h) Immunofluorescence staining shows localization of ILK (red) and the tubular cell marker lectin (green) in control (c–e) and diabetic kidneys (f–h), respectively. (i–n) Immunofluorescence staining demonstrates tubular EMT in diabetic nephropathy, as illustrated by colocalization of α-smooth muscle actin (red) and lectin (green) in diabetic kidneys (l–n) (arrowheads). (i–k) Control kidney. Scale bar, 20 μm.
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