Role of renal proximal tubule transport in thiazolidinedioneinduced volume expansion

作     者：George Seki Yoko Endo Masashi Suzuki Hideomi Yamada Shoko Horita Toshiro Fujita 

作者机构：Department of Internal Medicine Faculty of Medicine University of Tokyo 7-3-1 Bunkyo-ku Hongo Tokyo 113-0033 Japan 

出 版 物：《World Journal of Nephrology》 (世界肾病学杂志（英文版）)

年 卷 期：2012年第1卷第5期

页      面：146-150页

学科分类：1007[医学-药学(可授医学、理学学位)] 10[医学] 

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

摘      要：Thiazolidinediones （TZDs）, pharmacological activa-tors 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 contro-versy. Originally, PPARγ-mediated enhanced transcrip-tion 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 absorp-tion 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 fbroblast cells confrmed the existence of PPARγ/Src-dependent non-genomic signaling, which requires the ligand binding ability but not the transcriptional activity of PPARγ. The TZD-in-duced enhancement of association between PPARγ and Src supports an obligatory role for Src in this signal-ing. 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.