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

Frederikke Lihme Egerod, Jette Eldrup Svendsen, Jennifer Hinley, Jennifer Southgate, Annette Bartels, Nils Bruenner, Martin B. Oleksiewicz

Research output: Contribution to journalArticlepeer-review

Abstract

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 microheterogencity 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.

Original languageEnglish
Pages (from-to)947-958
Number of pages12
JournalExperimental and toxicologic pathology : official journal of the Gesellschaft für Toxikologische Pathologie
Volume37
Issue number7
DOIs
Publication statusPublished - Dec 2009

Keywords

  • dual-acting PPAR agonists
  • fenofibrate
  • rosiglitazone
  • rat urinary bladder cancer
  • Egr-1
  • PPAR alpha
  • PPAR gamma
  • kidney papilla
  • urothelium
  • receptor-mediated
  • PROSTATE TUMORIGENESIS
  • HEPARANASE EXPRESSION
  • TRANSCRIPTION FACTORS
  • ALPHA/GAMMA AGONIST
  • HYAL1 HYALURONIDASE
  • TUMOR PROMOTER
  • GROWTH-FACTORS
  • DUAL AGONISTS
  • IN-VIVO
  • CANCER

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