Proinflammatory Effect Of High Glucose Concentrations On Peritoneal Mesothelial Cell:The Role Of HMGB1-MAPK Pathway

BackgroundPeritoneal fibrosis,in which inflammation play crucial pathogenic roles,is a severe complication associated with the treatment of kidney failure with peritoneal dialysis(PD)using a glucose-based dialysate.Mesothelial cells(MCs)take part in the inflammatory processes by producing various cytokines and chemokines,such as monocyte chemoattractant protein 1(MCP-1)and interleukin 8(IL-8).High mobility group protein B1(HMGB1)is an inflammatory factor that has repeatedly been proven to be related to the occurrence of peritoneal dysfunction.AimIn this study,we aimed to explore the effect and underlying mechanism of endogenous HMGB1 in high-glucose-induced MC injury.MethodsThe human peritoneal MC line,HMrSV5 was cultured in high-glucose medium and incubated with recombinant HMGB1.Cellular expression of HMGB1 was blocked using HMGB1 small interfering RNA(siRNA).Production of inflammatory factors as well as the potential intermediary signaling pathways were examined.ResultsThe major findings of these analyses were:(1)MCs secreted HMGB1 from the nucleus during exposure to high glucose levels;(2)HMGB1 acted in an autocrine fashion on the MCs to promote the production of MCP-1 and IL-8;(3)HMGB1-mediated MCP-1 and IL-8 production depended on the activation of MAPK signaling pathways.ConclusionEndogenous HMGB1 plays an important role in the inflammatory reaction induced by high glucose on MCs via mitogen-activated protein kinase(MAPK)signaling pathways.These results demonstrate a new mechanism of high-glucose-induced inflammatory effects on MCs,which provide useful evidence to our understanding of how high concentrations of glucose,could exacerbate MC disruption and microenvironmental changes in peritoneal cavity.