Indoxyl Sulfate Induces Endothelial Cell Senescence by Increasing Reactive Oxygen Species Production and p53 Activity

Background/Aim We have reported that indoxylsulfate (IS), a uremic toxin, accelerates proximal tubular cell senescence. Asymmetric dimethylarginine(ADMA), an inhibitor of nitric oxide synthase, has been reported to induce endothelial cell senescence. This study aimed to determine whether IS induces endothelial cell senescencein comparison with ADMA, and to investigate its molecular mechanism. Methods Human umbilical vein endothelial cells(HUVECs) were incubated with IS (250 μM) and/or ADMA (10 μM). These concentrations were comparable with their mean serum levels in hemodialysis patients. Cell senescencewas evaluated by measuring senescence-associated beta-galactosidase(SA-β-gal) activity. N - acetylcysteine, an antioxidant, and pifithrinalpha p -nitro, a p53 inhibitor, were used to determine the role of reactive oxygen species (ROS) and p53 in the induction of cell senescence. Results Both IS and ADMA significantly increased SA-β-gal activity in HUVECs. Further, some additional increase in SA-β-gal activity was observed when IS and ADMA were co-incubated. Preincubation of N - acetylcysteineor pifithrinalpha p -nitro significantly inhibited SA-β-gal activity induced by IS and ADMA in HUVECs. Thus, both IS and ADMA induced endothelial senescencethrough ROS and p53. Conclusion IS induces endothelial cell senescenceby increasing ROS production and p53 activity, like ADMA.