Abstract
Thiazolidinediones (TZDs) are synthetic ligands for the nuclear peroxisome-proliferator activated receptor gamma (PPAR?). These agents have potent insulin-sensitizing capabilities and are used clinically for treatment of non-insulin dependent Type II diabetes mellitus. However, their use is limited in patients at risk for cardiovascular disease due to fluid retentive side effects. The side effect etiology is unknown, but the nature of presentation suggests modulation of renal salt and water homeostasis. This contention was strengthened by the creation of renal collecting duct specific PPAR? knockout animals that were resistant to the fluid retentive effects of two clinically used TZDs, rosiglitazone and pioglitazone. This renal site of action suggested a TZD effect on the epithelial Na+ channel (ENaC), a hormone regulated channel involved in fluid-electrolyte balance. However, several anomalies and conflicting data argue against an ENaC-mediated response as the primary target of PPAR? agonist-mediated fluid retention. In several collecting duct cell lines, we have shown that TZDs did not affect ENaC expression or activity. We have used the mpkCCDcl4 (mouse principal cells of the kidney cortical collecting duct, clone 4) cell line to show that PPAR? agonists inhibit vasopressin-stimulated Cl- secretion with agonist dose response relationships that mirror receptor trans-activation profiles. Analyses of the components of the vasopressin-stimulated intracellular signaling pathway indicated no PPAR? agonist-induced changes in basolateral membrane conductances, intracellular cAMP or protein kinase A. The PPAR? agonist-induced decrease in anion secretion is the result of decreased mRNA of the final effector in the pathway, the apically located cystic fibrosis transmembrane regulator (CFTR). These data showing that CFTR is a target for PPAR? agonists provides new insight into the physiology of PPAR? agonist-induced fluid retention. The data, if substantiated by in vivo experiments, indicate that CFTR can play a primary rather than secondary role in renal-mediated fluid balance. In addition, this finding may suggest potential treatment options for diseases in which CFTR activity plays a role. One of the most common of these is polycystic kidney disease (PKD). In PKD, CFTR-mediated Cl- secretion is known to contribute to the growth and maintenance of both renal and hepatic bile duct cysts. TZD inhibition of CFTR should, theoretically, inhibit cyst growth. Animal studies using an orthologous rat model of PKD are in progress. These studies can provide proof-of-principle for TZD-mediated CFTR inhibition as well as providing the basis for a new class of drug therapy for PKD.