Thiazolidinediones Enhance Sodium-Coupled Bicarbonate Absorption from Renal Proximal Tubules via PPARγ-Dependent Nongenomic Signaling

SummaryThiazolidinediones (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.

Graphical AbstractFigure optionsDownload high-quality image (228 K)Download as PowerPoint slideHighlights
► Stimulation of renal proximal transport by TZDs is dependent on PPARγ, Src, EGFR, and ERK
► Constitutive Src activity in mouse proximal tubules interferes with TZD's actions
► Nongenomic signaling does not require DNA-binding ability of PPARγ
► TZD-induced association between PPARγ and Src requires ligand-binding ability