Review
Copyright ©2012 Baishideng. All rights reserved.
World J Nephrol. Oct 6, 2012; 1(5): 146-150
Published online Oct 6, 2012. doi: 10.5527/wjn.v1.i5.146
Role of renal proximal tubule transport in thiazolidinedione-induced volume expansion
George Seki, Yoko Endo, Masashi Suzuki, Hideomi Yamada, Shoko Horita, Toshiro Fujita
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
Author contributions: All authors contributed to the conception and design of this study and the drafting of the manuscript, and approved the final version.
Correspondence to: George Seki, MD, Department of Internal Medicine, Faculty of Medicine, University of Tokyo, 7-3-1 Bunkyo-ku, Hongo, Tokyo 113-0033, Japan. georgeseki-tky@umin.ac.jp
Telephone: +81-3-38155411-33004 Fax: +81-3-58008806
Received: August 9, 2011
Revised: May 30, 2012
Accepted: September 25, 2012
Published online: October 6, 2012
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.

Keywords: Thiazolidinediones; Peroxisome-proliferator-activated receptors γ; Volume expansion; Edema; NBCe1; NHE3; Epithelial Na channel