Abstract

Background: The liver renin-angiotensin system (RAS) plays an important role in promoting the development of hepatic fibrogenesis. Angiotensinogen (AGT) is an important precursor in tissue RAS. This study aimed to investigate the expression and cellular source of AGT in hepatic fibrogenesis and its effect on proliferation and collagen metabolism of hepatic stellate cells.
Material/Methods: In a rat carbon tetrachloride (CCl4)-induced liver fibrosis model the mRNA expression of AGT was determined by real-time PCR and the cellular source of AGT was determined by immunohistochemical staining. In vitro HSC-T6 cells were transfected with AGT, and the expression plasmid, AGT shRNA plasmid and negative shRNA plasmid were constructed. Real-time PCR and ELISA were applied to determine the mRNA expressions and contents of TIMP-1, TGF-β1, type I collagen and type III collagen of the cells or in the supernatants.
Results: Compared to normal liver, the AGT and α-SMA mRNA expressions increased at the early stage of hepatic fibrosis and decreased in hepatic cirrhosis. The expressions of AGT and α-SMA mRNA were correlated with the hepatic fibrosis (r=0.915, P=0.03). Immunohistochemistry demonstrated the activated HSCs were the main source of AGT due to colocalization of AGT and α-SMA expressions. The mRNA and protein of TGF-β1, TIMP-1, type I collagen and type III collagen were markedly up-regulated.
Conclusions: ACEI and angiotensin II type 1 receptor antagonist (AT1RA) could attenuate the progression of hepatic fibrosis in the early stage. Direct inhibition of AGT from aHSCs may become an effective antifibrotic anti-liver fibrosis strategy.

Keywords: RNA, Messenger - metabolism, Liver Cirrhosis, Experimental - pathology, Liver - pathology, Hepatic Stellate Cells - pathology, Gene Expression Regulation, Extracellular Matrix - metabolism, Collagen - metabolism, Angiotensinogen - metabolism, Tissue Inhibitor of Metalloproteinase-1 - metabolism