Previous studies have reported that lipoxin A(4) (LXA(4)) may exert a renoprotective effect on ischemia/reperfusion injury in various animal models. The underlying mechanism of LXA(4)-induced renoprotection during ischemia/reperfusion injury remains to be elucidated. The present study investigated LXA4-induced protection on renal tubular cells subjected to hypoxia/reoxygenation (H/R) injury, and determined the effects of peroxisome proliferator-activated receptor-gamma (PPAR gamma) and heme oxygenase-1 (HO-1) on LXA(4) treatment. HK-2 human tubular epithelial cells exposed to H/R injury were pretreated with LXA4, signal molecule inhibitors or the HO-1 inhibitor zinc protoporphyrin-IX, or were transfected with PPAR. small interfering RNA (siRNA) or nuclear factor E2-related factor 2 (Nrf2) siRNA. The protein and mRNA expression levels of PPAR. and HO-1 were analyzed using western blotting and reverse transcription-quantitative polymerase chain reaction. Binding activity of Nrf2 to the HO-1 E1 enhancer was determined using chromatin immunoprecipitation. Nrf2 binding to the HO-1 antioxidant responsive element (ARE) was assessed using electrophoretic mobility shift assay. Preincubation of cells with LXA(4) exposed to H/R injury led to a decreased production of inducible nitrogen oxide synthase, malondialdehyde,gamma-glutamyl transpeptidase, leucine aminopeptidase and N-acetyl-gamma-glucosaminidase. In addition, LXA(4) pretreatment increased cell viability, protein and mRNA expression levels of PPAR. and HO-1 and PPAR. and HO-1 promoter activity. SB20358 is a p38 mitogen-activated protein kinase (p38 MAPK) pathway inhibitor, which reduced LXA(4)-induced PPAR. expression levels. LXA4 treatment upregulated p38 MAPK activation, Nrf2 nuclear translocation and increased binding activity of Nrf2 to HO-1 ARE and E1 enhancer in cells exposed to H/r injury. Transfection of thecells with PPAR gamma siRNA reduced the LXA(4)-induced Nrf2 translocation. Transfection of the cells with PPAR. siRNA or Nrf2 siRNA also reduced the LXA(4)-induced increase in HO-1 expression. In conclusion, LXA(4)-induced protection of renal tubular cells against H/R injury was associated with the induction of PPAR. and HO-1, via activation of the p38 MAPK pathway, as well as Nrf2 nuclear translocation and binding to HO-1 ARE and E1 enhancer. Therefore, LXA(4)-induced renoprotection is associated with activation of the p38 MAPK/PPAR gamma/Nrf2-ARE/HO-1 pathway.