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Inhibition of Integrin-Linked Kinase Attenuates Renal Interstitial Fibrosis

Yingjian Li^*, Xiaoyue Tan^*, Chunsun Dai^*, Donna B. Stolz, Dan Wang^* and Youhua Liu^*

Departments of *Pathology and
Cell Biology and Physiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania

Correspondence: Dr. Youhua Liu, Department of Pathology, University of Pittsburgh, S-405 Biomedical Science Tower, 200 Lothrop Street, Pittsburgh, PA 15261. Phone: 412-648-8253; Fax: 412-648-1916; E-mail: liuy{at}upmc.edu

Received for publication September 4, 2008. Accepted for publication April 16, 2009.

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-β1 and examined the therapeutic potential of an ILK inhibitor in obstructive nephropathy. TGF-β1 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-β1–induced phosphorylation of Akt and glycogen synthase kinase-3β, suppressed cyclin D1 expression, and largely restored the expression of E-cadherin and zonula occludens 1. Inhibition of ILK also blocked TGF-β1–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 β-catenin accumulation; suppressed Snail1, -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.

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Copyright © 2009 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673