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

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.

Figure 1

Effect of Pioglitazone on renal cysts in PCK rat model. The images show transverse sections of kidneys from animals that had been fed for 7 or 14 weeks with normal chow (control) or chow supplemented with pioglitazone to approximate a daily treatment of 4 or 20 mg/kg BW as indicated on the figure.

Figure 2

Immunostaining for CFTR in the liver of control and pioglitazone-treated PCK rats after 14 weeks of drug treatment. Control (a) or 20 mg/kg BW pioglitazone-treated (b) liver sections were immunostained for CFTR using mAb 596. Shown in both panels is the CFTR staining (brown) in the apical membranes of cyst-lining biliary epithelial cells. 1000x magnification.

Figure 3

Immunostaining for CFTR in the liver of control and pioglitazone-treated PCK rats after 14 weeks of drug treatment. Control (a) or 20 mg/kg BW pioglitazone-treated (b) liver sections were immunostained for CFTR with mAb 596 CFTR antibody followed by a gold-labeled secondary antibody. Shown in both panels is the CFTR staining (spherical dots) in the apical membrane sections of epithelial cells surrounding the bile duct cysts. 49 000x magnification.