PPARγ ligands suppress proliferation of human urothelial basal cells in vitro

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Abstract
Expression of peroxisome proliferator‐activated receptor (PPAR) γ in the human urinary tract through embryonic development suggests its possible roles in the development, proliferation, and differentiation of uroepithelium. Little is known, however, about physiological roles of PPARγ in the urinary tract. We investigated effects of PPARγ ligands on the proliferation of normal human urothelial cells and stromal cells cultivated from surgical specimens. Active proliferation in vitro as well as high molecular weight cytokeratin expression indicated that cultured urothelial cells possess basal cell phenotype. PPARγ protein, expressed predominantly in the epithelial layer of the normal human urinary tract in vivo, was abundantly expressed in urothelial cells but barely detectable in stromal cells in vitro. Natural ligand for PPARγ, 15‐deoxy‐Δ12,14 prostaglandin J2 (15d‐PGJ2), as well as synthetic ones, troglitazone and pioglitazone, suppressed proliferation of the urothelial cells dose‐dependently. These effects were PPARγ specific because clofibrate or PGF2α did not affect proliferation of urothelial cells. Neither 9‐cis retinoic acid or all‐trans retinoic acid (ATRA) at 1 μM showed any synergism on the antiproliferative effects of PPARγ ligands. Urothelial cells treated with PPARγ ligands showed drastic morphologic changes and cell cycle arrest at G0/G1 phase accompanied with increased mRNA level of a cyclin‐dependent kinase inhibitor p21(WAF1/CIP1). Since 15d‐PGJ2 is present in vivo during the resolution phase of inflammation, these results indicated that PPARγ might be involved in the terminal phase of urothelial re‐epithelialization processes.

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