RNA interference targeting the platelet-derived growth factor receptor β subunit ameliorates experimental hepatic fibrosis in rats


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Abstract

Background/AimsPlatelet-derived growth factor (PDGF) is the strongest stimulator of the proliferation of hepatic stellate cells (HSCs). PDGF receptor β subunit (PDGFR-β) is acquired on HSCs proliferation induced by PDGF. In this study, we aim to investigate the effect of PDGFR-β small interference RNA (siRNA) on experimental hepatic fibrosis.MethodsWe constructed a PDGFR-β siRNA expression plasmid and investigated its effect on the activation of HSCs. Bromodeoxyuridine incorporation was performed to investigate the effect of PDGFR-β siRNA on HSCs proliferation. A hydrodynamics-based transfection method was used to deliver PDGFR-β siRNA to rats with hepatic fibrosis. The distribution of transgenes in the liver was observed by immunofluorescence. The antifibrogenic effect of PDGFR-β siRNA was investigated pathologically.ResultsPlatelet-derived growth factor receptor-β subunit siRNA could significantly downregulate PDGFR-β expression, suppress HSCs activation, block the mitogen-activated protein kinase signalling pathway and inhibit HSCs proliferation in vitro. PDGFR-β siRNA expression plasmid could be delivered into activated HSCs by the hydrodynamics-based transfection method, and remarkably improve the liver function of the rat model induced by dimethylnitrosamine and bile duct ligation. Furthermore, the progression of fibrosis in the liver was significantly suppressed by PDGFR-β siRNA in both animal models.ConclusionsPlatelet-derived growth factor receptor-β subunit siRNA may be presented as an effective antifibrogenic gene therapeutic method for hepatic fibrosis.

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