Department of Internal Medicine, University of Tokyo, Bunkyo-ku, Hongo, Japan.
Cell Metab. 2011 May 4;13(5):550-61. doi: 10.1016/j.cmet.2011.02.015.
Thiazolidinediones (TZDs) improve insulin resistance by activating a nuclear hormone receptor, peroxisome proliferator-activated receptor γ (PPARγ). 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 PPARγ-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 PPARγ-Src-dependent nongenomic signaling, which requires the ligand-binding ability, but not the transcriptional activity of PPARγ, is confirmed in mouse embryonic fibroblast cells. The enhancement of the association between PPARγ and Src by TZDs supports an indispensable role of Src in this signaling. These results suggest that the PPARγ-dependent nongenomic stimulation of renal proximal transport is also involved in TZD-induced volume expansion.
噻唑烷二酮类（TZDs）通过激活核激素受体过氧化物酶体增殖物激活受体γ（PPARγ）来改善胰岛素抵抗。然而，TZDs 的使用与通过尚未阐明的机制导致的血浆容量扩张有关。在这里，我们显示 TZDs 可在体外和体内迅速刺激肾脏近端小管中的钠偶联碳酸氢盐吸收。TZD 诱导的转运刺激依赖于 PPARγ-Src-EGFR-ERK，并且在大鼠、兔和人中观察到，但在 Src-EGFR 持续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存在需要配体结合能力但不需要 PPARγ 转录活性的 PPARγ-Src 依赖性非基因组信号转导。TZDs 增强了 PPARγ 和 Src 之间的关联，支持 Src 在该信号转导中的不可或缺作用。这些结果表明，肾脏近端转运的 PPARγ 依赖性非基因组刺激也参与了 TZD 诱导的容量扩张。
