摘要
AIM:To study the role of advanced glycation end products(AGE)and their specifi c receptor(RAGE)in the pathogenesis of liver fi brogenesis.METHODS:In vitro RAGE expression and extracellular matrix-related gene expression in both rat and human hepatic stellate cells(HSC)were measured after stimulation with the two RAGE ligands,advanced glycation end product-bovine serum albumin(AGE-BSA)and Nε-(carboxymethyl)lysine(CML)-BSA,or with tumor necrosis factor-α(TNF-α).In vivo RAGE expression was examined in models of hepatic fi brosis induced by bile duct ligation or thioacetamide.The effects of AGE-BSA and CML-BSA on HSC proliferation,signal transduction and profi brogenic gene expression were studied in vitro.RESULTS:In hepatic fibrosis,RAGE expression was enhanced in activated HSC,and also in endothelial cells,inflammatory cells and activated bile duct epithelia.HSC expressed RAGE which was upregulated after stimulation with AGE-BSA,CML-BSA,and TNF-α.RAGE stimulation with AGE-BSA and CML-BSA did not alter HSC proliferation,apoptosis,fibrogenic signal transduction and fibrosis-or fibrolysis-related gene expression,except for marginal upregulation of procollagen α1(Ⅰ)mRNA by AGE-BSA.CONCLUSION:Despite upregulation of RAGE in activated HSC,RAGE stimulation by AGE does not alter their fibrogenic activation.Therefore,RAGE does not contribute directly to hepatic fibrogenesis.
AIM: To study the role of advanced glycation end products (AGE) and their specific receptor (RAGE) in the pathogenesis of liver fibrogenesis. METHODS: In vitro RAGE expression and extracellular matrix-related gene expression in both rat and human hepatic stellate cells (HSC) were measured after stimulation with the two RAGE ligands, advanced glycation end product-bovine serum albumin (AGE- BSA) and N'-(carboxymethyl) lysine (CML)-BSA, or with tumor necrosis factor-α (TNF-α). In vivo RAGE expression was examined in models of hepatic fibrosis induced by bile duct ligation or thioacetamide. The effects of AGE-BSA and CML-BSA on HSC proliferation, signal transduction and profibrogenic gene expression were studied in vitro. RESULTS: In hepatic fibrosis, RAGE expression was enhanced in activated HSC, and also in endothelial cells, inflammatory cells and activated bile duct epithelia. HSC expressed RAGE which was upregulated after stimulation with AGE-BSA, CML-BSA, and TNF-α.RAGE stimulation with AGE-BSA and CML-BSA did not alter HSC proliferation, apoptosis, fibrogenic signal transduction and fibrosis- or fibrolysis-related gene expression, except for marginal upregulation of procollagen α1( I ) mRNA by AGE-BSA. CONCLUSION: Despite upregulation of RAGE in activated HSC, RAGE stimulation by AGE does not alter their fibrogenic activation. Therefore, RAGE does not contribute directly to hepatic fibrogenesis.
基金
Supported by Grants from the Interdisciplinary Center for Clinical Research(IZKF,Project B39)
the Johannes and Frieda Marohn Foundation of the University of Erlangen-Nuremberg,Germany
关键词
糖基化终产物
肝纤维化
最终产品
受体
牛血清白蛋白
肿瘤坏死因子-Α
细胞外基质
晚期
Advanced glycation end product
Extracellularmatrix
Hepatic stellate cell
Matrix metalloproteinase
Myofibroblast
Receptor for advanced glycation endproducts
Transforming growth factor β
Tissue inhibitorof metalloproteinase
Tumor necrosis factor α