title: Inhibition of cyst growth in PCK and Wpk rat models of polycystic kidney disease with low doses of peroxisome proliferator-activated receptorγagonists.
abstract: OBJECTIVE
  The studies were designed to test the efficacy of two peroxisome proliferator-activated receptor γ (PPARγ) agonists in two rodent models of polycystic kidney disease (PKD).
  
  
  METHODS
  The PCK rat is a slowly progressing cystic model while theWpk-/-rat is a rapidly progressing model. PCK rats were fed with a pharmacological (0.4 mg/kg body weight [BW]) and a sub-pharmacological (0.04 mg/kg BW) dose of rosiglitazone (week 4-28).Wpk-/-rats were fed with pharmacological (2.0 mg/kg BW) and sub-pharmacologic (0.2 mg/kg BW) doses of pioglitazone from day 5 to 18. At termination, kidney weights of treated versus untreated cystic animals were used to determine efficacy. The current studies were also compared with previous studies containing higher doses of PPARγ agonists. The concentrations used in the animals were calculated with reference to equivalent human doses for both drugs.
  
  
  RESULTS
  The current studies demonstrate: 1) that low, pharmacologically relevant, doses of the PPARγ agonists effectively inhibit cyst growth; 2) there is a class action of the drugs with both commercially available PPARγ agonists, rosiglitazone, and pioglitazone, inhibiting cyst growth; 3) the drugs showed efficacy in two different preclinical cystic models. In the PCK rat, animals fed with a sub-pharmacological dose of rosiglitazone for 24 weeks had significantly lower kidney weights than untreated animals (3.68 ± 0.13 gvs. 4.17 ± 0. 11 g, respectively,P< 0.01) while treatment with a pharmacologic dose had no significant effect on kidney weight. The rapidly progressingWpk-/-rats were fed with pharmacological and sub-pharmacologic doses of pioglitazone from day 5 to 18 and the kidneys were compared with non-treated, cystic animals. Kidney weights on the pharmacologic dose were not statistically lower than the untreated animals while rats fed a sub-pharmacologic dose showed a significant decrease compared with untreated animals (3.35 ± 0.15 g vs. 4.55 ± 0.46 g, respectively,P= 0.045).
  
  
  CONCLUSIONS
  Concentrations of PPARγ agonists below the human equivalent diabetic doses are effective in slowing cyst growth in two rodent models of PKD.
authors.affiliation: Biology Department, Indiana University Purdue University Indianapolis, IN 46202, United States of America.
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Flaig
authors.affiliation: Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN 46202, United States of America.
authors.forename: Vincent H
authors.initials: VH
authors.lastname: Gattone
authors.affiliation: Biology Department, Indiana University Purdue University Indianapolis, IN 46202, United States of America; Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN 46202, United States of America.
authors.forename: Bonnie L
authors.initials: BL
authors.lastname: Blazer-Yost
keywords: cystic fibrosis transmembrane conductance regulator; cystic kidneys; pioglitazone; polycystic kidney disease; rosiglitazone