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: Daisuke Yoshihara, Hiroki Kurahashi, Miwa Morita, Masanori Kugita, Yoshiyuki Hiki, Harold M Aukema, Tamio Yamaguchi, James P Calvet, Darren P Wallace, Shizuko Nagao
• Journal: American journal of physiology. Renal physiology (Am J Physiol Renal Physiol) Vol. 300 Issue 2 Pg. F465-74 (Feb 2011) ISSN: 1522-1466 [Electronic] United States
• PMID: 21147840 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Ki-67 Antigen
• PPAR gamma
• Thiazolidinediones
• Transforming Growth Factor beta
• Mitogen-Activated Protein Kinase Kinases
• Pioglitazone

Topics

• Animals
• Blood Urea Nitrogen
• Cell Proliferation (drug effects)
• Disease Models, Animal
• Disease Progression
• Female
• Ki-67 Antigen (analysis)
• Liver Cirrhosis (drug therapy)
• Liver Diseases (drug therapy)
• Male
• Mitogen-Activated Protein Kinase Kinases (analysis)
• PPAR gamma (agonists)
• Pioglitazone
• Polycystic Kidney, Autosomal Recessive (drug therapy)
• Rats
• Rats, Sprague-Dawley
• Thiazolidinediones (therapeutic use)
• Transforming Growth Factor beta (analysis)