Background Oxidative Stress and p38 mitogen-activated protein kinase (p38MAPK) play a vital role in renal fibrosis.Pioglitazone can protect kidney but the underlying mechanisms are less clear.The purpose of this study was to investigate the effect of pioglitazone on oxidative stress and whether the severity of oxidative stress was associated with the phosphorylation level of p38MAPK.Methods Rat mesangial cells were cultured and randomly assigned to control group,high glucose group and pioglitazone group.After 48-hour exposure,the supatants and ceils were collected.The protein levels of p22phox,p47phox,phosphorylated p38MAPK,total p38MAPK were measured by West blotting.The gene expressions of p22phox,p47phox were detected by RT-PCR.The levels of intracellular reactive oxygen species (ROS) were determined by flow cytometry.The levels of superoxide dismutase (SOD) and maleic dialdehyde (MDA) in the supatant were determined respectively.Results Compared with the control group,the expression levels of p22phox,p47phox,phospho-p38 and ROS significantly increased,activity of SOD decreased in high glucose group,while the level of MDA greatly increased (P ＜0.01).Pioglitazone significantly suppressed p22phox,p47phox expressions and oxidative stress induced by high glucose.The expressions of p22phox,p47phox,phospho-p38MAPK and ROS generation were markedly reduced after pioglitazone treatment (P ＜0.05).The activity of SOD in the the supatant increased (P ＜0.05),while the level of MDA decreased greatly by pioglitazone (P ＜0.05).The level of oxidative stress was associated with the phosphorylation level of p38MAPK (P ＜0.01).Conclusion Pioglitazone can inhibit oxidative stress through suppressing NADPH oxidase expression and p38MAPK phosphorylation.