Generalized cellular hypertrophy is induced by a dual-acting PPAR agonist in rat urinary bladder urothelium in vivo.
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.
Oleksiewicz
Martin B
MB
Novo Nordisk A/S, Novo Nordisk Park, Department of Virology and Molecular Toxicology, Maalov, Denmark. mboz@novonordisk.com
Thorup
Inger
I
Nielsen
Henriette S
HS
Andersen
Hanne V
HV
Hegelund
Anne Charlotte
AC
Iversen
Lars
L
Guldberg
Torben S
TS
Brinck
Peter R
PR
Sjogren
Ingrid
I
Thinggaard
Ulla K
UK
Jørgensen
Lis
L
Jensen
Marianne B
MB
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
D005456:Fluorescent Dyes; D010078:Oxazines; D047493:PPAR alpha; D047495:PPAR gamma; D010666:Phenylpropionates; D011506:Proteins; D016650:Fluorescein-5-isothiocyanate; C432703:ragaglitazar