Thiazolidinediones enhance sodium-coupled bicarbonate absorption from renal proximal tubules via PPARγ-dependent nongenomic signaling.

Abstract

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.

• Authors: Yoko Endo, Masashi Suzuki, Hideomi Yamada, Shoko Horita, Motoei Kunimi, Osamu Yamazaki, Ayumi Shirai, Motonobu Nakamura, Naoyuki Iso-O, Yuehong Li, Masumi Hara, Kazuhisa Tsukamoto, Nobuo Moriyama, Akihiko Kudo, Hayato Kawakami, Toshimasa Yamauchi, Naoto Kubota, Takashi Kadowaki, Haruki Kume, Yutaka Enomoto, Yukio Homma, George Seki, Toshiro Fujita
• Journal: Cell metabolism (Cell Metab) Vol. 13 Issue 5 Pg. 550-61 (May 04 2011) ISSN: 1932-7420 [Electronic] United States
• PMID: 21531337 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Inc. All rights reserved.

Chemical References

• Bicarbonates
• Cation Transport Proteins
• PPAR gamma
• Slc9a1 protein, mouse
• Sodium-Hydrogen Exchanger 1
• Sodium-Hydrogen Exchangers
• Thiazolidinediones
• Sodium
• EGFR protein, mouse
• ErbB Receptors
• src-Family Kinases
• Extracellular Signal-Regulated MAP Kinases

Topics

• Adipocytes (cytology, drug effects, metabolism)
• Animals
• Bicarbonates (metabolism)
• Blotting, Western
• Cation Transport Proteins (metabolism)
• Cell Differentiation (drug effects)
• Cells, Cultured
• Embryo, Mammalian (cytology, drug effects, metabolism)
• ErbB Receptors (metabolism)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Fibroblasts (cytology, drug effects, metabolism)
• Humans
• Immunoenzyme Techniques
• Immunoprecipitation
• Kidney Tubules, Proximal (cytology, drug effects, metabolism)
• Mice
• Mice, Inbred C57BL
• PPAR gamma (genetics, metabolism)
• Phosphorylation (drug effects)
• Rabbits
• Rats
• Rats, Wistar
• Signal Transduction (drug effects)
• Sodium (metabolism)
• Sodium-Hydrogen Exchanger 1
• Sodium-Hydrogen Exchangers (metabolism)
• Species Specificity
• Thiazolidinediones (pharmacology)
• src-Family Kinases (metabolism)