Sortilin Ameliorates Hepatic Microcirculatory Disturbance Induced By High Glucose Through RhoA/ROCK/NF-κB Signal Pathway

Objective To investigate the expression of sortilin in liver and the possible mechanism of sortilin in microcirculation disturbance of liver induced by high glucose from both experiments sortilin in vivo and in vitro.Methods A Wistar rat model of diabetic fatty liver was established.The histomorphological and basement membrane changes in the liver of each group were observed by HE staining and gomori methenaminutese silver staining,and immunohistochemistry was used to detect the difference in the expression of sortilin in each group of liver tissues.Culture rLSECs,and lentiviral sortilin overexpression vector(LV-Sortilin)was constructed and transfected into rLSECs.rLSECs were cultured in vitro and treated with high concentration of glucose(25m M for 24 h),and were interfered with ROCK inhibitor Y-27632 and NF-κB inhibitor PDTC,respectively.MTT colorimetric method was utilized to detect the activity of rLSECs.Western blotting and RT-PCR techniques were used to detect the expression levels of sortilin,RhoA,ROCKⅠ,p65,p-p65,LN and PLVAP.The experimental data were statistically analysed by SPSS 25.0 software.Results1.HE staining showed that obvious fat accumulation occurred in hepatocytes in diabetic fatty liver group,hepatocytes arranged in extreme disorder and lost normal structure.Gomori methenaminutese silver staining showed that hepatic basement membrane thickened and reticular fibers in hepatic portal vein fused,thickened and intertwined in diabetic fatty liver group.Immunohistochemical staining showed that the expression of sortilin in liver tissue of diabetic fatty liver group was significantly decreased.2.Under the intervention of high glucose,the expression of sortilin in rLSECs decreased(P <0.001),while the expression of LN and PLVAP increased(P <0.001).3.Transfection of rLSECs with lentiviral sortilin overexpression vector reversed the expression of LN and PLVAP induced by high glucose(P <0.001).4.The expression of LN and PLVAP decreased after the intervention of ROCK inhibitor Y-27632(P <0.001),and the expression of LN and PLVAP further decreased on the basis of Y-27632 intervention after the intervention of NF-κB inhibitor PDTC(P <0.001).Conclusions1.Under the condition of high glucose,the down-regulation of sortilin can up-regulate the expression of LN and PLVAP through RhoA/ROCK/NF-κB signal pathway,which can induce hepatic sinusoidal endothelial cell dysfunction and eventually lead to the disturbance of liver microcirculation.2.LV-Sortilin reduces the expression of LN and PLVAP induced by high glucose by inhibiting the RhoA/ROCK/NF-κB pathway,and ultimately attenuates the disturbance of liver microcirculation induced by high glucose.3.Sortilin activators and RhoA/ROCK/NF-κB pathway inhibitors may become new drugs for the treatment of related metabolic diseases.4.Sortilin is expected to become a new target for screening and treatment of diabetic fatty liver disease.