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 PPARgamma agonists, such as pioglitazone, and dual PPARgamma/PPARalpha 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. PPARgamma 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.
Suzuki
Shugo
S
Department of Pathology and Microbiology and the Eppley Institute for Cancer Research, University of Nebraska Medical Center, Omaha, Nebraska 68198-3135, USA.
Arnold
Lora L
LL
Pennington
Karen L
KL
Kakiuchi-Kiyota
Satoko
S
Wei
Min
M
Wanibuchi
Hideki
H
Cohen
Samuel M
SM
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D007004:Hypoglycemic Agents / Q000633:toxicity*; D008297:Male; D009929:Organ Size / Q000187:drug effects; D047495:PPAR gamma / Q000819:agonists*; D000077205:Pioglitazone; D051381:Rats; D017207:Rats, Sprague-Dawley; D045162:Thiazolidinediones / Q000633:toxicity* / Q000652:urine; D001743:Urinary Bladder / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D014545:Urinary Calculi / Q000378:metabolism / Q000648:ultrastructure; D019459:Urothelium / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure
D007004:Hypoglycemic Agents; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077205:Pioglitazone