Peroxisome proliferator-activated receptor-γ agonists repress epithelial sodium channel expression in the kidney

Borsting E, Cheng VP, Glass CK, Vallon V, Cunard R. Peroxisome proliferator-activated receptor-gamma agonists repress epithelial sodium channel expression in the kidney. Am J Physiol Renal Physiol 302: F540-F551, 2012. First published December 14, 2011; doi: 10.1152/ajprenal.00306.2011.-Thiazolidinediones (TZDs), known as peroxisome proliferator-activated receptor (PPAR) agonists, are used to treat type 2 diabetes. However, similar to 5% of patients experience the treatment-limiting side effect of edema. Studies have implicated activation of the epithelial sodium channel (ENaC) as a cause of TZD-induced fluid retention, although there have been conflicting reports. The goal of this study was to resolve the role of PPAR gamma in control of ENaC isoforms in the kidney. Herein, we demonstrate in mice that rosiglitazone (RGZ), a PPAR gamma ligand, increases body weight and abdominal fat pad fluid content and reduces hematocrit. Seven days of RGZ decreases ENaC alpha and ENaC beta mRNA and ENaC gamma protein expression in the kidney cortex, and acute treatment for 5 h with pioglitazone, another potent TZD, does not increase renal ENaC isoform mRNA or protein expression. Pioglitazone also decreases ENaC alpha and ENaC gamma mRNA expression in a cortical collecting duct cell line. As no direct transcriptional studies had been conducted, we examined the PPAR gamma-dependent regulation of ENaC. Pioglitazone represses ENaC gamma promoter activity, and this repression is partially relieved by inhibition of protein synthesis. Chromatin immunoprecipitation assays revealed that repression is associated with a decrease in histone H4K5 acetylation at the proximal ENaC gamma promoter. In summary, TZDs do not increase ENaC mRNA expression in the kidney, and in fact repress the ENaC gamma promoter via an indirect transcriptional mechanism.