title: 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-beta1. TGF-beta1 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-beta1-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.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, S-405 Biomedical Science Tower, 200 Lothrop Street, Pittsburgh, Pennsylvania 15261, USA.
authors.forename: Yingjian
authors.initials: Y
authors.lastname: Li
authors.forename: Junwei
authors.initials: J
authors.lastname: Yang
authors.forename: Chunsun
authors.initials: C
authors.lastname: Dai
authors.forename: Chuanyue
authors.initials: C
authors.lastname: Wu
authors.forename: Youhua
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D001672:Biocompatible Materials / Q000494:pharmacology; D015152:Blotting, Northern; D015153:Blotting, Western; D002460:Cell Line; D002465:Cell Movement; D003094:Collagen / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004848:Epithelium / Q000378:metabolism*; D005355:Fibrosis / Q000378:metabolism*; D019084:Fluorescent Antibody Technique, Indirect; D005799:Genes, Dominant; D006801:Humans; D007674:Kidney Diseases / Q000378:metabolism*; D007797:Laminin / Q000494:pharmacology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008648:Mesoderm / Q000378:metabolism*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010641:Phenotype; D010957:Plasmids / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D011509:Proteoglycans / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D051899:Smad2 Protein; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1; D000077191:Wortmannin; D048051:p38 Mitogen-Activated Protein Kinases; D000099200:Scaffold Protein ILK
chemical_list: D000730:Androstadienes; D001672:Biocompatible Materials; D003094:Collagen; D004268:DNA-Binding Proteins; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D007797:Laminin; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D020928:Mitogen-Activated Protein Kinases; D017346:Protein Serine-Threonine Kinases; D011509:Proteoglycans; D012333:RNA, Messenger; D051899:Smad2 Protein; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D000077191:Wortmannin; D048051:p38 Mitogen-Activated Protein Kinases; D000099200:Scaffold Protein ILK; C497782:SMAD2 protein, human; C497783:Smad2 protein, mouse; C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; C059485:matrigel