Inhibition of integrin-linked kinase attenuates renal interstitial fibrosis.
Integrin-linked kinase (ILK) is an intracellular serine/threonine protein kinase that regulates cell adhesion, survival, and epithelial-to-mesenchymal transition (EMT). In this study, we investigated the kinase activity of ILK during tubular EMT induced by TGF-beta1 and examined the therapeutic potential of an ILK inhibitor in obstructive nephropathy. TGF-beta1 induced a biphasic activation of ILK in renal tubular epithelial cells, with rapid activation starting at 5 min and the second wave of activation peaking at 24 h; the latter paralleled the induction of ILK protein expression. Pharmacologic inhibition of ILK with small-molecule inhibitor QLT-0267 abolished TGF-beta1-induced phosphorylation of Akt and glycogen synthase kinase-3beta, suppressed cyclin D1 expression, and largely restored the expression of E-cadherin and zonula occludens 1. Inhibition of ILK also blocked TGF-beta1-mediated induction of fibronectin, Snail1, plasminogen activator inhibitor 1, and matrix metalloproteinase 2. In a mouse model of obstructive nephropathy, administration of QLT-0267 inhibited beta-catenin accumulation; suppressed Snail1, alpha-smooth muscle actin, fibronectin, vimentin, and type I and type III collagen expression; and reduced total tissue collagen content. Inhibition of ILK did not affect kidney structure or function in normal mice. These findings suggest that increased ILK activity mediates EMT and the progression of renal fibrosis. Pharmacologic inhibition of ILK signaling may hold therapeutic potential for fibrotic kidney diseases.
Li
Yingjian
Y
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
Tan
Xiaoyue
X
Dai
Chunsun
C
Stolz
Donna B
DB
Wang
Dan
D
Liu
Youhua
Y
D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D005355:Fibrosis; D006801:Humans; D007684:Kidney Tubules / Q000201:enzymology / Q000473:pathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D008648:Mesoderm / Q000166:cytology / Q000201:enzymology; D051379:Mice; D008815:Mice, Inbred Strains; D009395:Nephritis, Interstitial / Q000378:metabolism* / Q000473:pathology*; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D014517:Ureteral Obstruction / Q000378:metabolism / Q000473:pathology; D051176:beta Catenin / Q000378:metabolism; D000099200:Scaffold Protein ILK
D004791:Enzyme Inhibitors; D020778:Matrix Metalloproteinase 2; D017395:Plasminogen Activator Inhibitor 1; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1; D051176:beta Catenin; D000099200:Scaffold Protein ILK; C495267:CTNNB1 protein, mouse; C051321:SERPINE1 protein, human; C000604407:SNAI1 protein, human; C000604429:Snai1 protein, mouse