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Inhibition of Integrin-linked Kinase Attenuates Renal Interstitial Fibrosis

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Specialty Nephrology
Date 2009 Jun 23
PMID 19541809
Citations 62
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Abstract

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.

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References
1.
El-Aouni C, Herbach N, Blattner S, Henger A, Rastaldi M, Jarad G . Podocyte-specific deletion of integrin-linked kinase results in severe glomerular basement membrane alterations and progressive glomerulosclerosis. J Am Soc Nephrol. 2006; 17(5):1334-44. DOI: 10.1681/ASN.2005090921. View

2.
Liu B, Li M, Zhang J, Liu X, Zhang X, Phillips A . Inhibition of integrin-linked kinase via a siRNA expression plasmid attenuates connective tissue growth factor-induced human proximal tubular epithelial cells to mesenchymal transition. Am J Nephrol. 2007; 28(1):143-51. DOI: 10.1159/000110019. View

3.
Hu K, Wu C, Mars W, Liu Y . Tissue-type plasminogen activator promotes murine myofibroblast activation through LDL receptor-related protein 1-mediated integrin signaling. J Clin Invest. 2007; 117(12):3821-32. PMC: 2082143. DOI: 10.1172/JCI32301. View

4.
Tan X, Li Y, Liu Y . Paricalcitol attenuates renal interstitial fibrosis in obstructive nephropathy. J Am Soc Nephrol. 2006; 17(12):3382-93. DOI: 10.1681/ASN.2006050520. View

5.
Troussard A, Costello P, Yoganathan T, Kumagai S, Roskelley C, Dedhar S . The integrin linked kinase (ILK) induces an invasive phenotype via AP-1 transcription factor-dependent upregulation of matrix metalloproteinase 9 (MMP-9). Oncogene. 2000; 19(48):5444-52. DOI: 10.1038/sj.onc.1203928. View