title: Role of renal proximal tubule transport in thiazolidinedione-induced volume expansion.
abstract: Thiazolidinediones (TZDs), pharmacological activators of peroxisome-proliferator-activated receptors γ (PPARγ), significantly improve insulin resistance and lower plasma glucose concentrations. However, the use of TZDs is associated with plasma volume expansion, the mechanism of which has been a matter of controversy. Originally, PPARγ-mediated enhanced transcription of the epithelial Na channel (ENaC) γ subunit was thought to play a central role in TZD-induced volume expansion. However, later studies suggested that the activation of ENaC alone could not explain TZD-induced volume expansion. We have recently shown that TZDs rapidly stimulate sodium-coupled bicarbonate absorption from renal proximal tubule (PT) in vitro and in vivo. TZD-induced transport stimulation was dependent on PPARγ/Src/EGFR/ERK, and observed in rat, rabbit and human. However, this stimulation was not observed in mouse PTs where Src/EGFR is constitutively activated. Analysis in mouse embryonic fibroblast cells confirmed the existence of PPARγ/Src-dependent non-genomic signaling, which requires the ligand binding ability but not the transcriptional activity of PPARγ. The TZD-induced enhancement of association between PPARγ and Src supports an obligatory role for Src in this signaling. These results support the view that TZD-induced volume expansion is multifactorial. In addition to the PPARγ-dependent enhanced expression of the sodium transport system(s) in distal nephrons, the PPARγ-dependent non-genomic stimulation of renal proximal transport may be also involved in TZD-induced volume expansion.
authors.affiliation: George Seki, Yoko Endo, Masashi Suzuki, Hideomi Yamada, Shoko Horita, Toshiro Fujita, Department of Internal Medicine, Faculty of Medicine, University of Tokyo, 7-3-1 Bunkyo-ku, Hongo, Tokyo 113-0033, Japan.
authors.forename: George
authors.initials: G
authors.lastname: Seki
authors.forename: Yoko
authors.initials: Y
authors.lastname: Endo
authors.forename: Masashi
authors.initials: M
authors.lastname: Suzuki
authors.forename: Hideomi
authors.initials: H
authors.lastname: Yamada
authors.forename: Shoko
authors.initials: S
authors.lastname: Horita
authors.forename: Toshiro
authors.initials: T
authors.lastname: Fujita
keywords: Edema; Epithelial Na channel; NBCe1; NHE3; Peroxisome-proliferator-activated receptors γ; Thiazolidinediones; Volume expansion