Therapeutic targeting of the PDGF and TGF-beta-signaling pathways in hepatic stellate cells by PTK787/ZK22258

Abstract

Stimulation of hepatic stellate cells (HSCs) by platelet-derived growth factor (PDGF) and transforming growth factor-beta1 (TGF-beta1) 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-beta1-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-beta1 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.