Pioglitazone Attenuates Cystic Burden in the PCK Rodent Model of Polycystic Kidney Disease

Bonnie L Blazer-Yost,Tracy Eggleston-Gulyas,Vincent Gattone,Xiaofang Wang,Vicente E Torres,Julie Haydon,Jey-Hsin Chen

doi:10.1155/2010/274376

Bonnie L Blazer-Yost, Tracy Eggleston-Gulyas + Show 5 more

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https://doi.org/10.1155/2010/274376

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Abstract

Polycystic kidney disease (PKD) is a genetic disorder characterized by growth of fluid-filled cysts predominately in kidney tubules and liver bile ducts. Currently, the clinical management of PKD is limited to cyst aspiration, surgical resection or organ transplantation. Based on an observation that PPARγ agonists such as pioglitazone and rosiglitazone decrease mRNA levels of a Cl− transport protein, CFTR (cystic fibrosis transmembrane conductance regulator), and the Cl− secretory response to vasopressin in cultured renal cells, it is hypothesized that PPARγ agonists will inhibit cyst growth. The current studies show that a 7- or 14-week pioglitazone feeding regimen inhibits renal and hepatic bile duct cyst growth in the PCK rat, a rodent model orthologous to human PKD. These studies provide proof of concept for the mechanism of action of the PPARγ agonists and suggest that this class of drugs may be effective in controlling both renal and hepatic cyst growth and fibrosis in PKD.

Highlights

Agonists of the peroxisome proliferator activator receptor gamma (PPARγ) have pleiotropic effects on intermediary metabolism
Based on an observation that PPARγ agonists such as pioglitazone and rosiglitazone decrease mRNA levels of a Cl− transport protein, CFTR, and the Cl− secretory response to vasopressin in cultured renal cells, it is hypothesized that PPARγ agonists will inhibit cyst growth
Studies in a cell culture model of the principal cell type of the distal nephron have demonstrated that PPARγ agonists inhibit cAMP-stimulated anion transport and the mRNA expression of the cystic fibrosis transmembrane conductance regulator (CFTR), a Cl− channel found in the apical membrane of this cell type [6]

Summary

Introduction

Agonists of the peroxisome proliferator activator receptor gamma (PPARγ) have pleiotropic effects on intermediary metabolism. Two of these agents, rosiglitazone and pioglitazone, are approved for clinical use as insulin-sensitizing agents in the treatment of type II diabetes. A renal collecting duct-specific knockout of PPARγ in rodent models abrogates the drug-induced fluid retention, suggesting that the effect arises from alterations in electrolyte and/or fluid transport in the distal nephron [4, 5]. ARPKD affects children in the neonatal period and is characterized by tubular dilation. Both forms of PKD have liver involvement with cysts that arise from cholangiocytes, an epithelial cell type lining the hepatic bile ducts

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