Thiazolidinediones Enhance Sodium-Coupled Bicarbonate Absorption from Renal Proximal Tubules via PPARγ-Dependent Nongenomic Signaling
Thiazolidinediones Enhance Sodium-Coupled Bicarbonate Absorption from Renal Proximal Tubules via PPARγ-Dependent Nongenomic Signaling
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DOI：
10.1016/j.cmet.2011.02.015
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发表时间：
2011-05-04
期刊：
影响因子：
29
通讯作者：
Fujita, Toshiro
中科院分区：
文献类型：
--
作者：
Endo, Yoko;Suzuki, Masashi;Fujita, Toshiro
噻唑烷二酮类（TZD）通过激活核激素受体过氧化物酶体增殖物激活受体γ（PPAR γ）改善胰岛素抵抗。然而，TZD的使用与血浆容量扩张有关，其机制仍有待澄清。在这里，我们表明，TZDs快速刺激钠偶联碳酸氢盐的吸收从肾近端小管在体外和体内。TZD诱导的转运刺激依赖于PPAR γ-Src-EGFR-ERK，并在大鼠、兔和人中观察到，但在Src-EGFR组成性激活的小鼠近端小管中未观察到。在小鼠胚胎成纤维细胞中证实了PPAR γ-Src依赖的非基因组信号传导的存在，该信号传导需要配体结合能力，但不需要PPAR γ的转录活性。TZDs增强了PPAR γ和Src之间的关联，支持Src在此信号传导中不可或缺的作用。这些结果表明，肾脏近端转运的PPAR γ依赖性非基因组刺激也参与TZD诱导的体积扩张。
Thiazolidinediones (TZDs) improve insulin resistance by activating a nuclear hormone receptor, peroxisome proliferator-activated receptor gamma (PPAR gamma). However, the use of TZDs is associated with plasma volume expansion through a mechanism that remains to be clarified. Here we showed that TZDs rapidly stimulate sodium-coupled bicarbonate absorption from the renal proximal tubule in vitro and in vivo. TZD-induced transport stimulation is dependent on PPAR gamma-Src-EGFR-ERK and observed in rat, rabbit and human, but not in mouse proximal tubules where Src-EGFR is constitutively activated. The existence of PPAR gamma-Src-dependent nongenomic signaling, which requires the ligand-binding ability, but not the transcriptional activity of PPAR gamma, is confirmed in mouse embryonic fibroblast cells. The enhancement of the association between PPAR gamma and Src by TZDs supports an indispensable role of Src in this signaling. These results suggest that the PPAR gamma-dependent nongenomic stimulation of renal proximal transport is also involved in TZD-induced volume expansion.