title: Stimulation of ENaC activity by rosiglitazone is PPARγ-dependent and correlates with SGK1 expression increase.
abstract: Thiazolidinediones (TZDs) are peroxisome proliferator-activated receptor gamma (PPARγ) agonists used to treat type 2 diabetes. TZD treatment induces side effects such as peripheral fluid retention, often leading to discontinuation of therapy. Previous studies have shown that PPARγ activation by TZD enhances the expression or function of the epithelial sodium channel (ENaC) through different mechanisms. However, the effect of TZDs on ENaC activity is not clearly understood. Here, we show that treating Xenopus laevis oocytes expressing ENaC and PPARγ with the TZD rosiglitazone (RGZ) produced a twofold increase of amiloride-sensitive sodium current (Iam), as measured by two-electrode voltage clamp. RGZ-induced ENaC activation was PPARγ-dependent since the PPARγ antagonist GW9662 blocked the activation. The RGZ-induced Iam increase was not mediated through direct serum- and glucocorticoid-regulated kinase (SGK1)-dependent phosphorylation of serine residue 594 on the human ENaC α-subunit but by the diminution of ENaC ubiquitination through the SGK1/Nedd4-2 pathway. In accordance, RGZ increased the activity of ENaC by enhancing its cell surface expression, most probably indirectly mediated through the increase of SGK1 expression.
authors.affiliation: Department of Physiology and Biophysics, Faculty of Medicine and Health Sciences, University of Sherbrooke, Sherbrooke, QC, Canada.
authors.forename: Stephane
authors.initials: S
authors.lastname: Renauld
authors.forename: Karine
authors.initials: K
authors.lastname: Tremblay
authors.forename: Siham
authors.initials: S
authors.lastname: Ait-Benichou
authors.forename: Maxime
authors.initials: M
authors.lastname: Simoneau-Roy
authors.forename: Hugo
authors.initials: H
authors.lastname: Garneau
authors.forename: Olivier
authors.initials: O
authors.lastname: Staub
authors.forename: Ahmed
authors.initials: A
authors.lastname: Chraïbi
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D053503:Epithelial Sodium Channels / Q000187:drug effects / Q000378:metabolism*; D017874:Immediate-Early Proteins / Q000378:metabolism*; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology*; D009865:Oocytes / Q000187:drug effects / Q000502:physiology*; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D000077154:Rosiglitazone; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013223:Statistics as Topic; D045162:Thiazolidinediones / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects; D014982:Xenopus laevis; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D053503:Epithelial Sodium Channels; D017874:Immediate-Early Proteins; D047495:PPAR gamma; D017346:Protein Serine-Threonine Kinases; D000077154:Rosiglitazone; D045162:Thiazolidinediones; D000099184:Serum-Glucocorticoid Regulated Kinases