Differential expression genes analyzed by cDNA array in the regulation of rat hepatic fibrogenesis.

Abstract

PURPOSE:

To analyze the gene expression pattern in rat hepatic fibrogenesis and further assess the role of some key genes during the pathological process.

METHODS:

Hepatic fibrosis was induced by intraperitoneal injection of dimethylnitrosamine or carbon tetrachloride (CCl(4)) injection subcutaneously in rats, and identification of the hepatic fibrosis related genes with cDNA microarray was performed. After some key genes up-regulated during the development of hepatic fibrosis were screened and confirmed, their effects on the function of the activated rat hepatic stellate cells (HSC) were assessed using the small interfering RNA (siRNA) technique.

RESULTS:

Using an Atlas rat cDNA array, a number of differentially expressed genes in fibrotic liver tissues were identified compared with non-diseased control. A total of 15 genes predominantly associated with the mitogen-activated protein kinase (MAPK) signal transduction pathway were upregulated in the fibrotic liver. Immunohistochemical study revealed that the expressions of both extracellular signal-regulated kinases (ERK) and ribosomal protein S6 kinase (RSK), two of the key genes in the MAPK pathway, were remarkably induced, which was closely correlated to that of collagen types I and III during the development of hepatic fibrosis. Transfection of siRNA targeting ERK1 mRNA (siERK1) into HSC led to a 66% and 72% reduction of ERK1 mRNA and protein expression, respectively. Furthermore, siERK1 exerted the inhibition of the proliferation of HSC, accompanied by the induction of HSC apoptosis and reduction of collagen types I and III. In addition, siERK1 abolished the effect of platelet-derived growth factor-BB on the proliferation of HSC.

CONCLUSIONS:

The present study provided strong evidence for the participation of the MAPK pathway in the pathogenesis of hepatic fibrosis. Selective targeting of ERK1 inhibitors to HSC might present as a novel strategy for the treatment of hepatic fibrosis.

• Authors: Hui Qiang, Yong Lin, Xin Zhang, Xin Zeng, Jian Shi, Yue-Xiang Chen, Miao-Fang Yang, Ze-Guang Han, Wei-Fen Xie
• Journal: Liver international : official journal of the International Association for the Study of the Liver (Liver Int) Vol. 26 Issue 9 Pg. 1126-37 (Nov 2006) ISSN: 1478-3223 [Print] United States
• PMID: 17032414 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Collagen
• Ribosomal Protein S6 Kinases
• Extracellular Signal-Regulated MAP Kinases
• Mitogen-Activated Protein Kinase 3

Topics

• Animals
• Apoptosis (drug effects)
• Cell Line
• Cell Proliferation (drug effects)
• Collagen (metabolism)
• Extracellular Signal-Regulated MAP Kinases (genetics)
• Gene Expression
• Gene Expression Profiling
• Liver (cytology, metabolism, physiology)
• Liver Cirrhosis, Experimental (genetics)
• MAP Kinase Signaling System
• Male
• Mitogen-Activated Protein Kinase 3 (antagonists & inhibitors, genetics, pharmacology)
• Oligonucleotide Array Sequence Analysis
• RNA Interference
• Rats
• Rats, Sprague-Dawley
• Ribosomal Protein S6 Kinases (genetics)
• Transcription, Genetic