PPAR alpha and PPAR gamma coactivation rapidly induces Egr-1 in the nuclei of the dorsal and ventral urinary bladder and kidney pelvis urothelium of rats.
To facilitate studies of the rat bladder carcinogenicity of dual-acting PPAR alpha+gamma agonists, we previously identified the Egr-1 transcription factor as a candidate carcinogenicity biomarker and developed rat models based on coadministration of commercially available specific PPAR alpha and PPAR gamma agonists. Immunohistochemistry for Egr-1 with a rabbit monoclonal antibody demonstrated that male vehicle-treated rats exhibited minimal urothelial expression and specifically, no nuclear signal. In contrast, Egr-1 was induced in the nuclei of bladder, as well as kidney pelvis, urothelia within one day (2 doses) of oral dosing of rats with a combination of 8 mg/kg rosiglitazone and 200 mg/kg fenofibrate (specific PPAR gamma and PPAR alpha agonists, respectively). These findings were confirmed by Western blotting using a different Egr-1 antibody. Egr-1 was induced to similar levels in the dorsal and ventral bladder urothelium, arguing against involvement of urinary solids. Egr-1 induction sometimes occurred in a localized fashion, indicating physiological microheterogeneity in the urothelium. The rapid kinetics supported that Egr-1 induction occurred as a result of pharmacological activation of PPAR alpha and PPAR gamma, which are coexpressed at high levels in the rat urothelium. Finally, our demonstration of a nuclear localization supports that the Egr-1 induced by PPAR alpha and PPAR gamma coactivation in the rat urothelium may be biologically active.
Egerod
Frederikke Lihme
FL
Cell and Antibody Analysis, Novo Nordisk A/S, Novo Nordisk Park, Maalov, Denmark.
Svendsen
Jette Eldrup
JE
Hinley
Jennifer
J
Southgate
Jennifer
J
Bartels
Annette
A
Brünner
Nils
N
Oleksiewicz
Martin B
MB
D000284:Administration, Oral; D000818:Animals; D015197:Carcinogenicity Tests; D002273:Carcinogens / Q000008:administration & dosage / Q000633:toxicity; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D051766:Early Growth Response Protein 1 / Q000378:metabolism*; D011345:Fenofibrate / Q000008:administration & dosage / Q000633:toxicity; D007682:Kidney Pelvis / Q000378:metabolism*; D008297:Male; D047493:PPAR alpha / Q000819:agonists* / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D051381:Rats; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000633:toxicity; D001743:Urinary Bladder / Q000378:metabolism*; D019459:Urothelium / Q000378:metabolism*
D002273:Carcinogens; D051766:Early Growth Response Protein 1; C486110:Egr1 protein, rat; D047493:PPAR alpha; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D011345:Fenofibrate