PPARα and PPARγ are co-expressed, functional and show positive interactions in the rat urinary bladder urothelium

• Published in: Journal of applied toxicology 2010-03, Vol.30 (2), p.151-162
• Main Authors: Egerod, Frederikke Lihme, Brünner, Nils, Svendsen, Jette E., Oleksiewicz, Martin B.
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Egr-1; Medical sciences; molecular toxicology; Nephrology. Urinary tract diseases; PMP70; preclinical carcinogenicity safety assessment; rat urinary bladder cancer; Toxicology; Tumors of the urinary system; Urinary system involvement in other diseases. Miscellaneous; Urinary tract. Prostate gland; urothelium
• ISSN: 0260-437X; 1099-1263
• DOI: 10.1002/jat.1481

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. PPARα and PPARγ exhibited positive interactions in the rat bladder urothelium, based on Western analysis of the the Egr‐1 and PMP70 candidate biomarkers in the bladder urothelium of rosiglitazone and fenofibrate‐treated rats. Males exhibited a higher PPARα/PPARγ expression balance in the bladder urothelium than females. Fenofibrate induced the peroxisome membrane protein PMP70 in the bladder urothelium. Our findings support that dual‐acting PPAR agonists could cause bladder cancer in rodents by receptor‐mediated mechanisms potentially also involving peroxisome proliferation and oxidative stress.