title: PPAR-gamma agonist ameliorates kidney and liver disease in an orthologous rat model of human autosomal recessive polycystic kidney disease.
abstract: In autosomal recessive polycystic kidney disease (ARPKD), progressive enlargement of fluid-filled cysts is due to aberrant proliferation of tubule epithelial cells and transepithelial fluid secretion leading to extensive nephron loss and interstitial fibrosis. Congenital hepatic fibrosis associated with biliary cysts/dilatations is the most common extrarenal manifestation in ARPKD and can lead to massive liver enlargement. Peroxisome proliferator-activated receptor γ (PPAR-γ), a member of the ligand-dependent nuclear receptor superfamily, is expressed in a variety of tissues, including the kidneys and liver, and plays important roles in cell proliferation, fibrosis, and inflammation. In the current study, we determined that pioglitazone (PIO), a PPAR-γ agonist, decreases polycystic kidney and liver disease progression in the polycystic kidney rat, an orthologous model of human ARPKD. Daily treatment with 10 mg/kg PIO for 16 wk decreased kidney weight (% of body weight), renal cystic area, serum urea nitrogen, and the number of Ki67-, pERK1/2-, and pS6-positive cells in the kidney. There was also a decrease in liver weight (% of body weight), liver cystic area, fibrotic index, and the number of Ki67-, pERK1/2-, pERK5-, and TGF-β-positive cells in the liver. Taken together, these data suggest that PIO inhibits the progression of polycystic kidney and liver disease in a model of human ARPKD by inhibiting cell proliferation and fibrosis. These findings suggest that PPAR-γ agonists may have therapeutic value in the treatment of the renal and hepatic manifestations of ARPKD.
authors.affiliation: Education and Research Center of Animal Models for Human Diseases, Fujita Health University, Toyoake, Aichi, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Yoshihara
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kurahashi
authors.forename: Miwa
authors.initials: M
authors.lastname: Morita
authors.forename: Masanori
authors.initials: M
authors.lastname: Kugita
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Hiki
authors.forename: Harold M
authors.initials: HM
authors.lastname: Aukema
authors.forename: Tamio
authors.initials: T
authors.lastname: Yamaguchi
authors.forename: James P
authors.initials: JP
authors.lastname: Calvet
authors.forename: Darren P
authors.initials: DP
authors.lastname: Wallace
authors.forename: Shizuko
authors.initials: S
authors.lastname: Nagao
mesh_terms: D000818:Animals; D001806:Blood Urea Nitrogen; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D019394:Ki-67 Antigen / Q000032:analysis; D008103:Liver Cirrhosis / Q000188:drug therapy; D008107:Liver Diseases / Q000188:drug therapy*; D008297:Male; D020929:Mitogen-Activated Protein Kinase Kinases / Q000032:analysis; D047495:PPAR gamma / Q000819:agonists*; D000077205:Pioglitazone; D017044:Polycystic Kidney, Autosomal Recessive / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D045162:Thiazolidinediones / Q000627:therapeutic use*; D016212:Transforming Growth Factor beta / Q000032:analysis
chemical_list: D019394:Ki-67 Antigen; D047495:PPAR gamma; D045162:Thiazolidinediones; D016212:Transforming Growth Factor beta; D020929:Mitogen-Activated Protein Kinase Kinases; D000077205:Pioglitazone