Vasonatrin peptide ameliorates hepatic fibrosis via NPR/cGMP/PKG signal transduction pathway

Abstract

Objective To investigate the effects and signal transduction pathway of vasonatrin peptide(VNP),a novel man-made natriuretic peptide,on hepatic fibrosis.Methods Mice were injec ted with carbon tetrachloride(CCl4)for 12 weeks,with or without VNP treatment in the last 6 weeks.HE staining and Sirius red staining were performed to evaluate the status of hepatic fibrosis.In vitro after treatment of VNP,and DNA and collagen synthesis of cultured HSC-T6 hepatic stellate cells were assessed by[3H]-thymidine and[3H]proline incorporation,respectively.The signaling pathway involved was identified by radioimmunoassay to detect the levels of intracellular cGMP,and by mimicking experiments using 8-br-cGMP(a membrane-permeable cGMP analog).Blocking experi ments were performed using HS-142-1,an antagonist of guanylyl cyclase-coupled natriuretic peptide receptor(NPR),or KT-5823,the cGMP-dependent protein kinase(PKG)inhibitor.Results VNP markedly alleviated CCl4-induced liver fibrosis in mice.In vitro,HSC-T6 cells demonstrated a dosedependent reduction of DNA and collagen synthesis in the presence of VNP.In addition,VNP significantly increased intracellular levels of cGMP.The effects of VNP were mimicked by 8-br-cGMP,but they were inhibited by HS-142-1,or KT-5823.Conclusion VNP ameliorated liver fibrosis by inhibiting collagen production from hepatic stellate cells via guanylyl cyclase-coupled NPR/cGMP/PKG signal pathway,indicating that VNP might be a new effective agent in the treatment of liver fibrosis. Key words: Natriuretic peptides; Hepatic fibrosis; Carbon tetrachloride