Background/Aims: Thiazolidinediones (TZD) are ligands known to bind to and activate the nuclear peroxisome proliferator-activated receptor γ (PPARγ), and are currently used as insulin sensitizers in type 2 diabetes. Recently, several studies have shown that TZD may have a role in renal protection in various experimental models. However, the precise mechanisms by which TZD may possibly affect tubular cell survival after injury remain unclear. We studied the influence of the TZD rosiglitazone on PPARγ expression and cell function with cellular damage induced by increasing hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>) concentrations in bovine renal tubular epithelial cells (bEPC) to determine whether rosiglitazone is cytoprotective under these conditions. Methods: bEPC were cultured in the presence of H<sub>2</sub>O<sub>2</sub> after pretreatment with or without 25 µ M rosiglitazone. The expression of PPARγ mRNA and protein were determined using RT-PCR or Western blots, respectively, after 6 and 24 h. Some cells also received actinomycin D or cycloheximide and PPARγ protein expression was tested. Proliferation rates of cultures were compared after 15 h and after a recovery phase of 6 days. Apoptosis was assessed by DNA fragmentation. Nuclear PPARγ activity was evaluated by electrophoretic mobility shift assay (EMSA), and the cellular location was detected using immunofluorescence. Results: Incubation of bEPC with H<sub>2</sub>O<sub>2</sub> concentrations up to 0.75 m M did not induce apoptosis as tested by DNA fragmentation assay, but significantly and dose-dependently reduced proliferation 15 h after injury as measured by [<sup>3</sup>H]thymidine incorporation. 25 µ M rosiglitazone alone also reduced proliferation and failed to attenuate the H<sub>2</sub>O<sub>2</sub>-mediated inhibition of proliferation. However, rosiglitazone facilitates recovery of tubular cells 6 days after H<sub>2</sub>O<sub>2</sub>-induced injury. Rosiglitazone (25 µ M) increased PPARγ mRNA and protein expression in bEPC in the absence of H<sub>2</sub>O<sub>2</sub>. Rosiglitazone failed to increase PPARγ mRNA in cells with oxidative stress, but Western blots revealed an increase in cellular PPARγ protein content in the presence of rosiglitazone and increasing concentrations of H<sub>2</sub>O<sub>2</sub>. This increase in PPARγ protein content was almost totally abolished in the presence of 1 µg/ml cycloheximide, but was only marginally reduced by 0.1 µg/ml actinomycin D. EMSA showed a robust increase in nuclear PPARγ protein binding in vitro to its consensus site after rosiglitazone whereas H<sub>2</sub>O<sub>2</sub> treatment reduced PPARγ activation. Rosiglitazone treatment of cells with oxidative stress preserved nuclear transactivation of PPARγ. Conclusions: Rosiglitazone increases the PPARγ content in bEPC after H<sub>2</sub>O<sub>2</sub>-induced injury by a posttranscriptional mechanism. Activation of PPARγ facilitates the long-term recovery of tubular cells 6 days after oxidative injury, but had no effect on the attenuated proliferation shortly after injury. TZD cannot prevent oxidative injury to tubular cells, but may be important mediators to enhance cellular recovery after oxidative stress.