Journal
LABORATORY INVESTIGATION
Volume 89, Issue 10, Pages 1152-1160Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/labinvest.2009.77
Keywords
Akt; HSC; PDGF; PTK787/ZK22258; TGF-beta 1
Categories
Funding
- Hong Kong Research Grants Council [PolyU 5407/06M, PolyU 5638/07M]
- Shenzhen Bureau of Science, Technology and Information (Shenzhen Key Laboratory Advancement Scheme)
- Small Project Funding Programme of the University of Hong Kong
- NIH [DK56621]
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Stimulation of hepatic stellate cells (HSCs) by platelet-derived growth factor (PDGF) and transforming growth factor-beta 1 (TGF-beta 1) is an essential pathway of proliferation and fibrogenesis, respectively, in liver fibrosis. We provide evidence that PTK787/ZK222584 (PTK/ZK), a potent tyrosine kinase inhibitor that blocks vascular endothelial growth factor receptor (VEGFR), significantly inhibits PDGF receptor expression, as well as PDGF-simulated HSC proliferation, migration and phosphorylation of ERK1/2, Akt and p70S6 kinase. Interestingly, PTK/ZK also antagonizes the TGF-beta 1-induced expression of VEGF and VEGFR1. Furthermore, PTK/ZK downregulates TGF-beta receptor expression, which is associated with reduced Akt, ERK and p38MAPK phosphorylation. Furthermore, PDGF-induced TGF-beta 1 expression is inhibited by PTK/ZK. These findings provide evidence that PTK/ZK targets multiple essential pathways of stellate cell activation that provoke proliferation and fibrogenesis. Our study underscores the potential use of PTK/ZK as an antifibrotic drug in chronic liver disease. Laboratory Investigation (2009) 89, 1152-1160; doi:10.1038/labinvest.2009.77; published online 10 August 2009
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