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Role of renal proximal tubule transport in thiazolidinedioneinduced volume expansion

World Journal of Nephrology 2012年第5期1卷 146-150页

作者： 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

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.

关键词： Thiazolidinediones Peroxisome-proliferator-activated receptors γ Volume expansion Edema NBCe1 NHE3 epithelial na channel

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