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PPARα and PPARγ are co‐expressed, functional and show positive interactions in the rat urinary bladder urothelium
Author(s) -
Egerod Frederikke Lihme,
Brünner Nils,
Svendsen Jette E.,
Oleksiewicz Martin B.
Publication year - 2010
Publication title -
journal of applied toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.784
H-Index - 87
eISSN - 1099-1263
pISSN - 0260-437X
DOI - 10.1002/jat.1481
Subject(s) - urothelium , rosiglitazone , fenofibrate , endocrinology , medicine , peroxisome proliferator activated receptor , urinary system , kidney , agonist , ppar agonist , urinary bladder , chemistry , receptor
Some dual‐acting PPARα + γ agonists cause cancer in the rat urinary bladder, in some cases overrepresented in males, by a mechanism suggested to involve chronic stimulation of PPARα and PPARγ, i.e. exaggerated pharmacology. By western blotting, we found that the rat urinary bladder urothelium expressed PPARα at higher levels than the liver and heart, and comparable to kidney. Urothelial expression of PPARγ was above that of fat, heart, skeletal muscle and kidney. Male rats exhibited a higher PPARα/PPARγ expression balance in the bladder urothelium than did female rats. Rats were treated by gastric gavage with rosiglitazone (PPARγ agonist), fenofibrate (PPARα agonist) or a combination of rosiglitazone and fenofibrate for 7 days. In the urothelium, the transcription factor Egr‐1 was induced to significantly higher levels in rats co‐administered rosiglitazone and fenofibrate than in rats administered either rosiglitazone or fenofibrate alone. Egr‐1 was also induced in the heart and liver of rats treated with fenofibrate, but a positive interaction between rosiglitazone and fenofibrate with regards to Egr‐1 induction was only seen in the urothelium. Thus, in the rat urinary bladder urothelium, PPARα and PPARγ were expressed at high levels, were functional and exhibited positive interactions. Interestingly, fenofibrate induced the peroxisome membrane protein PMP70 not only in liver, but also in the bladder urothelium, opening the possibility that oxidative stress may contribute to rat urothelial carcinogenesis by dual‐acting PPARα + γ agonists. Copyright © 2009 John Wiley & Sons, Ltd.