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.
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Article Nephrology

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

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 4

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Forced expression of ILK induces fibronectin expression and its extracel...
Forced expression of ILK induces fibronectin expression and its extracellular assembly. (a) Northern blot analysis shows that forced expression of ILK induces fibronectin (Fn) mRNA expression in tubular epithelial cells. Total RNA was isolated from different cell lines as indicated and hybridized with cDNA probes of fibronectin and GAPDH, respectively. Cont., control parental HKC cells; vector, HKC cells transplanted with empty vector. (b) Western blot demonstrates that either treatment with TGF-β1 or forced expression of ILK induced total fibronectin protein expression in tubular epithelial cells. Cell lysates were immunoblotted with Ab’s against fibronectin and actin, respectively. (c) Expression of ILK promotes the extracellular assembly of fibronectin. Extracellular protein extracts were prepared from various cells as indicated and subjected to Western blot analyses using fibronectin Ab. (d) Graphical presentation shows the effects of ILK expression on the relative extent of total fibronectin expression and its extracellular assembly. Data are presented as fold induction over the empty vector control cells. (e and f) Immunofluorescence staining demonstrates the extracellular assembly of fibronectin in tubular epithelial cells transfected with empty vector (e) or WT-ILK (f). Scale bar, 5 μm.