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, Hideki Wanibuchi, Samuel M. Cohen

Research output: Contribution to journalArticlepeer-review

77 Scopus citations


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.

Original languageEnglish (US)
Article numberkfp256
Pages (from-to)349-357
Number of pages9
JournalToxicological Sciences
Issue number2
StatePublished - Oct 25 2009


  • Differentiation
  • Peroxisome proliferator-activated receptor
  • Urinary bladder
  • Urinary solids
  • Urothelial cell cytotoxicity

ASJC Scopus subject areas

  • Toxicology


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