晚期糖基化终末产物通过膜突蛋白磷酸化诱导小鼠肝窦毛细血管形成OA

AIM:To investigate whether advanced glycation end products(AGEs)promote mouse liver sinu-soidal capillarization and hepatic fibrosis via inducing phosphorylation of moesin(encoded by Msn gene)in liver sinusoi-dal endothelial cells(LSECs),thereby contributing to the pathogenesis of diabetic-associated liver injury.METHODS:(1)C57BL/6 wild-type(WT)mice were randomly divided into three groups:control,bovine serum albumin(BSA)and AGE-BSA,with 4 mice in each group.The mice in the later two groups were treated with BSA and AGE-BSA,respective-ly,for 1 or 6 months,and HE staining was used to observe liver histopathological changes.Scanning electron microscopy and transmission electron microscopy were employed to examine LSECs fenestral structure,and immunohistochemistry was performed to detect CD31 and CD34 expression,and collagen type IV(Col-IV)deposition for evaluating liver sinusoidal capillarization.Moesin phosphorylation in liver tissues was also measured.(2)Msn gene knockout(Msn-/y)mice were treated with AGE-BSA for 1 or 6 months,with 4 mice in each group,and then their liver fibrosis degree,functional indica-tors and pathological changes were assessed and compared with those in AGE-BSA-treated WT mice.RESULTS:Treat-ment with AGE-BSA induced histological abnormalities in WT mouse livers with damaged LSEC fenestration,and signifi-cantly increased CD31 and CD34 expression alongside Col-IV deposition(P<0.05),indicating sinusoidal capillarization.These changes were accompanied by hepatic fibrosis and mild hepatic dysfunction(P<0.05).Elevated phosphorylation of moesin was observed in the liver of AGE-BSA-treated WT mice(P<0.05).In Msn-/y mice,AGE-BSA-induced damages in liver architecture were alleviated,with decreased CD31 and CD34 expression and reduced Col-IV deposition.CONCLU-SION:The AGEs can promote sinusoidal capillarization,hepatic fibrosis and liver dysfunction in mouse liver tissues.Phosphorylation of moesin in LSECs represents a key molecular mechanism mediating AGE-induced liver injury in mice.