title: Generalized cellular hypertrophy is induced by a dual-acting PPAR agonist in rat urinary bladder urothelium in vivo.
abstract: Some developmental dual-acting PPARalpha/gamma agonists, such as ragaglitazar, have shown carcinogenic effects in the rodent urinary bladder urothelium after months-years of dosing. We examined early (precancerous) changes in the bladder urothelium of rats orally dosed with ragaglitazar, using a newly developed flow cytometric method. Following 3 weeks of oral ragaglitazar dosing, increases in physical size occurred in a generalized fashion in rat bladder urothelial cells, determined by flow cytometry. Protein/DNA measurements confirmed increased protein content of urothelial cells in the bladder, and hypertrophy was observed in the kidney pelvis urothelium by histopathology. In animals exhibiting urothelial hypertrophy, no cell cycle changes were detected in parallel samples of bladder urothelium. Interestingly, urothelial cells from normal rats were found to constitute a unique type of noncycling population, with high G2/M fractions. In summary, our findings showed that in the urothelium of ragaglitazar-treated animals, hypertrophy (increased size and protein content per cell) was an early change, that affected the whole bladder urothelial cell population. The urothelial hypertrophy was primary, i.e., occurred in the absence of similarly pronounced changes in cell cycle distributions. To our knowledge, this is the first report of a direct hypertrophic effect of a PPAR agonist. Urothelial hypertrophy might be a relevant early biological endpoint in mechanistic studies regarding the bladder-carcinogenic effect of PPAR agonists.
authors.affiliation: Novo Nordisk A/S, Novo Nordisk Park, Department of Virology and Molecular Toxicology, Maalov, Denmark. mboz@novonordisk.com
authors.forename: Martin B
authors.initials: MB
authors.lastname: Oleksiewicz
authors.forename: Inger
authors.initials: I
authors.lastname: Thorup
authors.forename: Henriette S
authors.initials: HS
authors.lastname: Nielsen
authors.forename: Hanne V
authors.initials: HV
authors.lastname: Andersen
authors.forename: Anne Charlotte
authors.initials: AC
authors.lastname: Hegelund
authors.forename: Lars
authors.initials: L
authors.lastname: Iversen
authors.forename: Torben S
authors.initials: TS
authors.lastname: Guldberg
authors.forename: Peter R
authors.initials: PR
authors.lastname: Brinck
authors.forename: Ingrid
authors.initials: I
authors.lastname: Sjogren
authors.forename: Ulla K
authors.initials: UK
authors.lastname: Thinggaard
authors.forename: Lis
authors.initials: L
authors.lastname: Jørgensen
authors.forename: Marianne B
authors.initials: MB
authors.lastname: Jensen
mesh_terms: D000818:Animals; D002453:Cell Cycle; D005434:Flow Cytometry; D016650:Fluorescein-5-isothiocyanate; D005456:Fluorescent Dyes; D006984:Hypertrophy / Q000139:chemically induced; D008297:Male; D008856:Microscopy, Fluorescence; D010078:Oxazines / Q000494:pharmacology*; D047493:PPAR alpha / Q000819:agonists*; D047495:PPAR gamma / Q000819:agonists*; D010666:Phenylpropionates / Q000494:pharmacology*; D011506:Proteins / Q000032:analysis; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D001743:Urinary Bladder / Q000473:pathology*; D019459:Urothelium
chemical_list: D005456:Fluorescent Dyes; D010078:Oxazines; D047493:PPAR alpha; D047495:PPAR gamma; D010666:Phenylpropionates; D011506:Proteins; D016650:Fluorescein-5-isothiocyanate; C432703:ragaglitazar