¹Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai, China

Correspondence: Professor W-F Xie, Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, 415 Fengyang Road, Shanghai 200003, China. E-mail: weifenxie@medmail.com.cn

²These authors contributed equally to this work.

Received 19 November 2007; Revised 21 April 2008; Accepted 22 April 2008; Published online 29 May 2008.

Abstract

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- subunit (PDGFR-) is required for the proliferation of HSCs induced by PDGF. In this study, a high gene-silencing-efficacy PDGFR- small interference RNA (siRNA) was synthesized that could suppress the PDGFR- 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-, we constructed an HSCs-specific short hairpin RNA (shRNA) expression plasmid in which PDGFR- 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- shRNA could relieve liver injury and hepatic fibrosis in the rat's model induced by BDL. This study demonstrates that PDGFR- 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.