Abstract

The rennin-angiotensin system (RAS) is crucial in hepatic fibrosis development, and therapies targeting this system may be a promising treatment for hepatic fibrosis. In this study, we investigated the effects of swertiamarin (Swe), an ethanol extract of Gentiana manshurica Kitag, on hepatic fibrosis and its underlying mechanisms through regulating RAS. Primary rat hepatic stellate cells (HSCs) were isolated and treated with angiotensin II (Ang II) with or without Swe and losartan. The proliferation and activation of HSCs were measured. Rat hepatic fibrosis was induced by intraperitoneal dimethylnitrosamine (DMN) injection for 4 weeks. Rats were treated with Swe or losartan from the 3rd week until the end of the experiment. Hydroxyproline (Hyp) content in liver tissue was assayed with Jamall's method and liver collagen deposition was visualized using sirius red staining. RAS components were analyzed by western blot, immunofluorescent staining, and real time RT-PCR. The results showed that Swe significantly inhibited Ang II-induced HSCs proliferation and activation. Swe also significantly suppressed DMN-induced alpha-smooth muscle actin production in rat liver and improved liver function. Swe partially inhibited Ang II-induced angiotensin type 1 receptor (AT1R) upregulation and suppressed Ang II-induced ERK and c-jun phosphorylation in HSCs. In the DMN-treated rats, Swe treatment significantly inhibited the plasma Ang II levels. DMN-induced AT1R upregulation and phosphorylation of ERK and c-jun in rat liver were also inhibited by Swe. In conclusion, Swe may attenuate hepatic fibrosis through inhibiting HSC activation by regulating the RAS.