Aim To investigate the effect of advanced glycation end products modified human serum albumin(AGE-HSA) on morphological changes of tight junction associated protein ZO-1 in endothelial cell and the mechanism in this pathological procedure. Methods Human umbilical vein endothelial cell(hUVEC)-derived cell line(ECV304) were incubated with AGE-HSA in different concentrations and timing. To visualize the morphological changes of tight junction protein ZO-1,the treated cell were incubated with mouse anti-ZO-1 primary antibody and then FITCanti-mouse IgG secondary antibody.The morphological changes of ZO-1 were observed with confocal microscope.The cell were pre-administrated with PD98059,a specific inhibitor of MEK1(ERK upstream kinase)or SB₂03580,a specific inhibitor of p38 MAP kinase,respectively,before exposed to AGE-HSA,then the cell were rinsed with DMEM for three times and exposed to AGE-HSA. The cell were transfected with dominant negative MEK1 or MEK6b(p38 upstream kinase) mutant adenoviruse,then exposed to AGE-HSA.And the cell were transfected with constitutively active MEK1 or MEK6b mutant adenoviruse. Results In normal control group,ZO-1 staining appeared as a continuous and smooth line along the regions of cell cell contact.Under the stimulation of AGE HSA,morphology of ZO-1 in endothelial cell were changed greatly in a concentration and time-dependent manner.The changes were partially blocked by PD98059 and SB₂03580.The transfection of dominant negative MEK1 and MEK6b mutant adenoviruse had the similar effects.The transfection of constitutively active MEK1 and MEK6b disrupted the structure of ZO-1. Conclusion AGE modified proteins can induce morphological changes of ZO-1 in endothelial cell.Activations of ERK and p38 MAP kinase pathways play an important role in this procedure.