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

Abstract

BACKGROUND/AIMS:

Platelet-derived growth factor (PDGF) is the strongest stimulator of the proliferation of hepatic stellate cells (HSCs). PDGF receptor beta subunit (PDGFR-beta) is acquired on HSCs proliferation induced by PDGF. In this study, we aim to investigate the effect of PDGFR-beta small interference RNA (siRNA) on experimental hepatic fibrosis.

METHODS:

We constructed a PDGFR-beta siRNA expression plasmid and investigated its effect on the activation of HSCs. Bromodeoxyuridine incorporation was performed to investigate the effect of PDGFR-beta siRNA on HSCs proliferation. A hydrodynamics-based transfection method was used to deliver PDGFR-beta siRNA to rats with hepatic fibrosis. The distribution of transgenes in the liver was observed by immunofluorescence. The antifibrogenic effect of PDGFR-beta siRNA was investigated pathologically.

RESULTS:

Platelet-derived growth factor receptor-beta subunit siRNA could significantly downregulate PDGFR-beta expression, suppress HSCs activation, block the mitogen-activated protein kinase signalling pathway and inhibit HSCs proliferation in vitro. PDGFR-beta 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-beta siRNA in both animal models.

CONCLUSIONS:

Platelet-derived growth factor receptor-beta subunit siRNA may be presented as an effective antifibrogenic gene therapeutic method for hepatic fibrosis.

• Authors: Si-Wen Chen, Xing-Rong Zhang, Chong-Ze Wang, Wei-Zhong Chen, Wei-Fen Xie, Yue-Xiang Chen
• Journal: Liver international : official journal of the International Association for the Study of the Liver (Liver Int) Vol. 28 Issue 10 Pg. 1446-57 (Dec 2008) ISSN: 1478-3231 [Electronic] United States
• PMID: 18466260 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA Primers
• RNA, Small Interfering
• Receptor, Platelet-Derived Growth Factor beta
• Bromodeoxyuridine

Topics

• Animals
• Blotting, Western
• Bromodeoxyuridine
• Cell Line
• Cell Proliferation
• DNA Primers (genetics)
• Fluorescent Antibody Technique
• Gene Expression Regulation (genetics)
• Genetic Therapy (methods)
• Hepatic Stellate Cells (metabolism)
• Liver Cirrhosis, Experimental (genetics, metabolism, therapy)
• RNA Interference
• RNA, Small Interfering (genetics)
• Rats
• Rats, Sprague-Dawley
• Receptor, Platelet-Derived Growth Factor beta (genetics, metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Transfection (methods)