| 18509379 |
Chen SW, Chen YX, Zhang XR, Qian H, Chen WZ, Xie WF: Targeted inhibition of platelet-derived growth factor receptor-beta subunit in hepatic stellate cells ameliorates hepatic fibrosis in rats. Gene Ther. 2008 Nov;15(21):1424-35. Epub 2008 May 29.
The activation of hepatic stellate cells (HSCs) is the key event of the pathogenesis of hepatic fibrosis. Platelet-derived growth factor (PDGF) is the most potent mitogen for HSCs, and PDGF receptor-beta subunit (PDGFR-beta) is required for the proliferation of HSCs induced by PDGF. In this study, a high gene-silencing-efficacy PDGFR-beta small interference RNA (siRNA) was synthesized that could suppress the PDGFR-beta expression and inhibit the activation and proliferation but could not induce the apoptosis of HSCs in vitro. To avoid the side effect of nonspecific interference of PDGFR-beta, we constructed an HSCs-specific short hairpin RNA (shRNA) expression plasmid in which PDGFR-beta shRNA was driven by a glial fibrillary acidic protein (GFAP) promoter. The double-staining immunofluorescence examination indicated that GFAP promoter could target the transgene expression into HSCs in carbon tetrachloride induced acute injured rat's liver and bile duct ligation (BDL)-induced chronic injured rat's liver. Furthermore, HSCs-specific PDGFR-beta shRNA could relieve liver injury and hepatic fibrosis in the rat's model induced by BDL. This study demonstrates that PDGFR-beta siRNA may be presented as an antifibrogenic agent. The application of HSCs-specific RNA interference induced by the GFAP promoter might supply a new powerful tool for cell-specific gene therapy of hepatic fibrogenesis. |
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