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

¹ Jack Birch Unit of Molecular Carcinogenesis, Department of Biology, University of York, York, Y010 5YW, UK
² Molecular Toxicology, Novo Nordisk A/S, Maalov, Denmark

Correspondence: Address correspondence to: Professor Jennifer Southgate, Jack Birch Unit of Molecular Carcinogenesis, Department of Biology, University of York, York Y010 5YW, UK; e-mail:js35{at}york.ac.uk.

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 RXR and RXRβ isoforms in a predominantly nuclear localization, indicating that they may be biologically active. However, immunolocalization differences were observed between species. First, whereas PPAR and PPARβ/ were expressed throughout the human bladder or ureteric urothelium, in the rat urothelium PPAR was primarily, and PPARβ/ 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, PPAR 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.

Key Words: bladder • Ki67 • lower urinary tract • PPAR • RXR • urothelium

Abbreviations: CK, cytokeratin • FDA, Food and Drug Administration • FITC, fluorescein isothiocyanate • KSFM, keratinocyte serum free medium • LUT, lower urinary tract • NHU, normal human urothelial • NRU, normal rat urothelial • PPAR, peroxisome proliferator-activated receptors • PPRE, peroxisome proliferator response element • RXR, retinoid X receptor • TZDs, thiazolidine-diones • UP, uroplakin

This version was published on April 1, 2008

Toxicologic Pathology, Vol. 36, No. 3, 485-495 (2008)
DOI: 10.1177/0192623308315672


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