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ToxSci Advance Access published online on October 25, 2009
Toxicological Sciences, doi:10.1093/toxsci/kfp256
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© The Author 2009. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

Effects of Pioglitazone, a Peroxisome Proliferator-Activated Receptor Gamma Agonist, on the Urine and Urothelium of the Rat

Shugo Suzuki*, Lora L. Arnold*, Karen L. Pennington*, Satoko Kakiuchi-Kiyota*, Min Wei{dagger}, Hideki Wanibuchi{dagger} and Samuel M. Cohen*,1

* Department of Pathology and Microbiology and the Eppley Institute for Cancer Research, University of Nebraska Medical Center, Omaha, Nebraska 68198-3135 {dagger} Department of Pathology, Osaka City University Medical School, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585, Japan 1 Havlik-Wall Professor of Oncology

Corresponding author: Dr. Samuel M. Cohen, Telephone: (402) 559-6388, Fax: (402) 559-9297, E-mail: scohen{at}unmc.edu

Received September 14, 2009; revision received October 8, 2009; accepted October 13, 2009


  Abstract

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors which belong to the nuclear receptor superfamily. Some PPAR{gamma} agonists, such as pioglitazone, and dual PPAR{gamma}/PPAR{alpha} agonists, such as muraglitazar, induced urothelial bladder tumors in rats but not in mice. In this study, we investigated the early effects in the urine and bladder of rats treated with pioglitazone to evaluate the possible relation between urinary solids formation and urothelial cytotoxicity and regenerative proliferation. In a 4-week experiment, treatment of rats with 16 mg/kg pioglitazone induced cytotoxicity and necrosis of the urothelial superficial layer, with increased cell proliferation measured by bromodeoxyurindine labeling index and hyperplasia by histology. It also produced alterations in urinary solid formation, especially calcium-containing crystals and calculi. PPAR{gamma} agonists (pioglitazone and troglitazone) in vitro reduced rat urothelial cell proliferation and induced uroplakin synthesis, a specific differentiation marker in urothelial cells. Our data support the hypothesis that the bladder tumors produced in rats by pioglitazone are related to the formation of urinary solids. This strongly supports the previous conclusion in studies with muraglitazar that this is a rat specific phenomenon and does not pose a urinary bladder cancer risk to humans treated with these agents.

Key Words: Peroxisome proliferator-activated receptor (PPAR); urinary bladder; urothelial cell cytotoxicity; urinary solids; differentiation.


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