Peroxisome proliferator-activated receptor-[gamma] agonists repress epithelial sodium channel expression in the kidney

Thiazolidinediones (TZDs), known as peroxisome proliferator-activated receptor (PPAR) agonists, are used to treat type 2 diabetes. However, ~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... in control of ENaC isoforms in the kidney. Herein, we demonstrate in mice that rosiglitazone (RGZ), a PPAR... ligand, increases body weight and abdominal fat pad fluid content and reduces hematocrit. Seven days of RGZ decreases ENaC... and ENaC... mRNA and ENaC... 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... and ENaC... mRNA expression in a cortical collecting duct cell line. As no direct transcriptional studies had been conducted, we examined the PPAR...-dependent regulation of ENaC. Pioglitazone represses ENaC... 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... promoter. In summary, TZDs do not increase ENaC mRNA expression in the kidney, and in fact repress the ENaC... promoter via an indirect transcriptional mechanism. (ProQuest: ... denotes formulae/symbols omitted.)