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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Li, Yingjian Tan, Xiaoyue Dai, Chunsun Stolz, Donna B. Wang, Dan Liu, Youhua |
| Description | Country affiliation: United States Author Affiliation: Li Y ( Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.) |
| 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. |
| File Format | HTM / HTML |
| ISSN | 10466673 |
| e-ISSN | 15333450 |
| DOI | 10.1681/ASN.2008090930 |
| Journal | Journal of the American Society of Nephrology |
| Issue Number | 9 |
| Volume Number | 20 |
| Language | English |
| Publisher | American Society of Nephrology |
| Publisher Date | 2009-09-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Discipline Nephrology Nephritis, Interstitial Metabolism Pathology Protein-serine-threonine Kinases Antagonists & Inhibitors Animals Cells, Cultured Disease Models, Animal Enzyme Inhibitors Pharmacology Epithelial Cells Cytology Drug Effects Enzymology Fibrosis Kidney Tubules Matrix Metalloproteinase 2 Genetics Mesoderm Mice Mice, Inbred Strains Plasminogen Activator Inhibitor 1 Rna, Messenger Transcription Factors Transforming Growth Factor Beta1 Ureteral Obstruction Beta Catenin Research Support, N.i.h., Extramural Research Support, Non-u.s. Gov't |
| Content Type | Text |
| Resource Type | Article |
| Subject | Nephrology |
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