Augmentation of cadmium-induced oxidative cytotoxicity by pioglitazone in renal tubular epithelial cells

The aim of this study was to examine whether a peroxisome proliferator-activated receptor (PPAR)-gamma agonist could affect cadmium (Cd)-induced cytotoxicity via the increased expression of megalin, one of the uptake pathways, using renal epithelial LLC-PK1 cells. The treatment with 1 mu M Cd for 24 h was not cytotoxic; however, when the cells were pretreated with 0.1 mu M pioglitazone for 12 h and then exposed to 1 mu M Cd for 24 h, significant accumulation of Cd and cytotoxicity were detected, with an increase in megalin mRNA expression. In addition, pretreatment with pioglitazone significantly increased the Cd-induced generation of hydrogen peroxide and cell apoptosis. The augmented Cd-induced cytotoxicity and apoptosis on preincubation with pioglitazone were inhibited by prior treatment with GW 9662 (PPAR-gamma antagonist). These findings suggest that a PPAR-gamma agonist could augment Cd-induced oxidative injury and cell apoptosis, possibly dependent on the expression level of the uptake pathway.