title: 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.affiliation: Department of Internal Medicine, University of Tokyo, Bunkyo-ku, Hongo, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Endo
authors.forename: Masashi
authors.initials: M
authors.lastname: Suzuki
authors.forename: Hideomi
authors.initials: H
authors.lastname: Yamada
authors.forename: Shoko
authors.initials: S
authors.lastname: Horita
authors.forename: Motoei
authors.initials: M
authors.lastname: Kunimi
authors.forename: Osamu
authors.initials: O
authors.lastname: Yamazaki
authors.forename: Ayumi
authors.initials: A
authors.lastname: Shirai
authors.forename: Motonobu
authors.initials: M
authors.lastname: Nakamura
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Iso-O
authors.forename: Yuehong
authors.initials: Y
authors.lastname: Li
authors.forename: Masumi
authors.initials: M
authors.lastname: Hara
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Tsukamoto
authors.forename: Nobuo
authors.initials: N
authors.lastname: Moriyama
authors.forename: Akihiko
authors.initials: A
authors.lastname: Kudo
authors.forename: Hayato
authors.initials: H
authors.lastname: Kawakami
authors.forename: Toshimasa
authors.initials: T
authors.lastname: Yamauchi
authors.forename: Naoto
authors.initials: N
authors.lastname: Kubota
authors.forename: Takashi
authors.initials: T
authors.lastname: Kadowaki
authors.forename: Haruki
authors.initials: H
authors.lastname: Kume
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Enomoto
authors.forename: Yukio
authors.initials: Y
authors.lastname: Homma
authors.forename: George
authors.initials: G
authors.lastname: Seki
authors.forename: Toshiro
authors.initials: T
authors.lastname: Fujita
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001639:Bicarbonates / Q000378:metabolism*; D015153:Blotting, Western; D027682:Cation Transport Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects*; D012964:Sodium / Q000378:metabolism*; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism; D013045:Species Specificity; D045162:Thiazolidinediones / Q000494:pharmacology*; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D001639:Bicarbonates; D027682:Cation Transport Proteins; D047495:PPAR gamma; C490997:Slc9a1 protein, mouse; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers; D045162:Thiazolidinediones; D012964:Sodium; C541485:EGFR protein, mouse; D066246:ErbB Receptors; D019061:src-Family Kinases; D048049:Extracellular Signal-Regulated MAP Kinases