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

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors, which belong to the nuclear receptor superfamily. Some PPARγ agonists, such as pioglitazone, and dual PPARγ/PPARα agonists, such as muraglitazar, induced urothelial bladder tumors in rats but not in mice....

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Published in:Toxicological sciences 2010-02, Vol.113 (2), p.349-357
Main Authors: Suzuki, Shugo, Arnold, Lora L., Pennington, Karen L., Kakiuchi-Kiyota, Satoko, Wei, Min, Wanibuchi, Hideki, Cohen, Samuel M.
Format: Article
Language:English
Subjects:
Animals
Body Weight - drug effects
Gene Expression - drug effects
Hypoglycemic Agents - toxicity
Male
Organ Size - drug effects
PPAR gamma - agonists
Rats
Rats, Sprague-Dawley
Thiazolidinediones - toxicity
Thiazolidinediones - urine
Urinary Bladder - drug effects
Urinary Bladder - metabolism
Urinary Bladder - ultrastructure
Urinary Calculi - metabolism
Urinary Calculi - ultrastructure
Urothelium - drug effects
Urothelium - metabolism
Urothelium - ultrastructure
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Summary:Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors, which belong to the nuclear receptor superfamily. Some PPARγ agonists, such as pioglitazone, and dual PPARγ/PPARα 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 bromodeoxyuridine labeling index and hyperplasia by histology. It also produced alterations in urinary solid formation, especially calcium-containing crystals and calculi. PPARγ 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.
ISSN:1096-6080
1096-0929
DOI:10.1093/toxsci/kfp256