The urotension II antagonist SB-710411 arrests fibrosis in CCL4 cirrhotic rats.

Urotensin II (UII) is a relatively novel peptide that functions as a potent vasoactive mediator throughout the human body, and also possesses mitogenic and fibrogenic potential. Recent reports showed increased plasma levels of UII in human cirrhotic populations; these levels were correlated with the severity of the disease. We therefore hypothesized that the blockade of UII signaling would arrest the progression of hepatic fibrosis in a rat model of cirrhosis. Cirrhosis was induced in rats by carbon tetrachloride. SB-710411 was used as the UII antagonist. Treatment lasted 8 weeks. Plasma hyaluronic acid (HA) and laminin (LN) were evaluated by radioimmunoassay, and plasma UII was determined by ELISA for the quantity of hydroxyproline (Hyp) in the liver tissues. Fibrosis was assessed histologically. The activated hepatic stellate cells (HSCs) were assessed by α-smooth muscle actin innunostaining. The relative mRNA expression of UII/G protein-coupled receptor (UT), collagen I, collagen III, transforming growth factor β1 (TGF-β1) and tissue inhibitor of metalloproteinase-1 (TIMP-1) in the liver was determined by real-time reverse transcriptase-polymerase chain reaction. Western blot analysis was used to assess liver levels of UT. The mitogenic activity of UII on HSC-T6 cells was also evaluated. Animals with cirrhosis showed increased plasma UII. UII/UT mRNA expression was up-regulated in the liver. Plasma levels of UII were also positively correlated with HA, LN and Hyp. In vivo, treatment with SB-710411 significantly reduced fibrosis development and down-regulated the profibrogenic cytokines TGF-β1 and TIMP-1. In vitro, UII induced the proliferation of HSCs. This mitogenic effect was significantly inhibited by 10-3 M SB-710411 (p<0.05). These data suggest that the selective blockade of UT has an arresting effect on fibrosis progression in vivo, and inhibits UII-mediated HSC proliferation in vitro.