Trans-Species Comparison of PPAR and RXR Expression by Rat and Human Urothelial Tissues

Because some investigational peroxisome proliferator-activated receptors (PPAR) agonists cause tumors in the lower urinary tract of rats, we compared normal human and rat urothelium in terms of PPAR and retinoid X receptor (RXR) expression and proliferation-associated phenotypes. In situ, few human but most rat urothelial cells were Ki67 positive, indicating fundamental differences in cell cycle control. Rat and human urothelia expressed all 3 PPAR and the RXRα and RXRβ isoforms in a predominantly nuclear localization, indicating that they may be biologically active. However, immunolocalization differences were observed between species. First, whereas PPARα and PPARβ/δ were expressed throughout the human bladder or ureteric urothelium, in the rat urothelium PPARα was primarily, and PPARβ/δ exclusively, restricted to superficial cells. Second, RXRβ was restricted to intermediate and superficial layers of the human urothelium but tended to be absent from the rat superficial cells. Third, PPARγ expression was present throughout the urothelia of both species but was most intense in the superficial human urothelium. Species differences were also observed in the expression of PPAR and RXR isoforms between cultured rat and human urothelial cells and in the smooth muscle. Our findings highlight the unique coexpression of multiple PPAR and RXR isoforms by urothelium and suggest that species differences in PPAR function between rat and human urothelia may be explored in an in vitro setting.