title: Peroxisome proliferator-activated receptor-γ agonists repress epithelial sodium channel expression in the kidney.
abstract: 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 PPARγ in control of ENaC isoforms in the kidney. Herein, we demonstrate in mice that rosiglitazone (RGZ), a PPARγ ligand, increases body weight and abdominal fat pad fluid content and reduces hematocrit. Seven days of RGZ decreases ENaCα and ENaCβ mRNA and ENaCγ 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 ENaCα and ENaCγ mRNA expression in a cortical collecting duct cell line. As no direct transcriptional studies had been conducted, we examined the PPARγ-dependent regulation of ENaC. Pioglitazone represses ENaCγ 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 ENaCγ promoter. In summary, TZDs do not increase ENaC mRNA expression in the kidney, and in fact repress the ENaCγ promoter via an indirect transcriptional mechanism.
authors.affiliation: Research and Medicine Services, Div. of Nephrology, Veterans Affairs San Diego Healthcare System, San Diego, CA 92161, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Borsting
authors.forename: Vicki Pei-Chun
authors.initials: VP
authors.lastname: Cheng
authors.forename: Chris K
authors.initials: CK
authors.lastname: Glass
authors.forename: Volker
authors.initials: V
authors.lastname: Vallon
authors.forename: Robyn
authors.initials: R
authors.lastname: Cunard
mesh_terms: D050153:Abdominal Fat / Q000187:drug effects; D000107:Acetylation; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D053503:Epithelial Sodium Channels / Q000235:genetics / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D047495:PPAR gamma / Q000819:agonists*; D000077205:Pioglitazone; D011401:Promoter Regions, Genetic; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*
chemical_list: D053503:Epithelial Sodium Channels; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D000077205:Pioglitazone