Effects of AT1 receptor antagonist, losartan, on rat hepatic fibrosis induced by CCl(4)

Abstract

AIM:To investigate effect of losartan, an AT1 receptor antagonist, on hepatic fibrosis induced by CCl(4); and to determine whether or not AT1 receptors are expressed on hepatic stellate cells. METHODS AND RESULTS:Fifty male Sprague-Dawley rats, weighing (180 plus minus20)g, were randomized into five groups (control group, model group, and three losartan treated groups), in which all rats were given the subcutaneous injection of 40% CCl(4)(every 3 days for 6 weeks) except for rats of control group. Rats of losartan-treated groups were treated with losartan (20 mg/kg, 10 mg/kg, 5 mg/kg, daily gavage). After 6 weeks liver tissue and serum samples of all rats were examined. Serum hyaluronic acid (HA), procollagen type III (PC III) were detected by radioimmunoassays. van Giesion collagen staining was used to evaluate the extracellular matrix of rats with liver fibrosis. The expression of AT1 receptors, transforming growth factor-beta (TGF-beta), and alpha-smooth muscle actinalpha-SMA) in liver tissue were determined by immunohistochemical techniques. Compared with model group, serum ALT and AST of losartan-treated groups were significantly reduced (italic>t = 4.20,P < 0.01 and italic>t = 4.57,P < 0.01). Serum HA and PC III also had significant differences (italic>t = 3.53,P<0.01 and t=2.20, P<0.05). The degree of fibrosis was improved by losartan and correlated with the expressions of AT1 receptors, TGF-beta, and alpha-SMA in liver tissue.CONCLUSION:AT1 receptor antagonist, losartan, could limit the progression of the hepatic fibrosis induced by CCl(4). The mechanism may be related to the decrease in the expression of AT1 receptors and TGF-beta, ameliorating the injury of hepatocytes; activation of local renin-angiotensin system might relate to hepatic fibrosis; and during progression of fibrosis, activated hepatic stellate cells might express AT1 receptors.

Figure 1

Collagen expression in liver section of model rat (van Gieson staining, × 200) (A), and of losartan treated group (van Giesion staining, × 200). Significantly less fibrosis can be noted compared to that in the model group (B).

Figure 2

AT1 receptor expression in liver section of model rat (DAB staining, × 200). AT1 receptor is seen mainly scattered in fibrotic areas and vascular wal l (A), and of los artan treated group (DAB staining, × 200). Note significantly less AT1 expression than that seen in the model group (B).

Figure 3

TGF-β expression in liver section of model rat ( DAB staining, × 200). TGF-β expression is seen scattered in the fibrotic areas and vascular wall (A), and of losart an treated group (DAB staining, × 200). Note significantly less TGF-β expression than that seen in the model group (B).