title: CFTR mediates cadmium-induced apoptosis through modulation of ROS level in mouse proximal tubule cells.
abstract: The aim of this study was to characterize the role of CFTR during Cd(2+)-induced apoptosis. For this purpose primary cultures and cell lines originated from proximal tubules (PCT) of wild-type cftr(+/+) and cftr(-/-) mice were used. In cftr(+/+) cells, the application of Cd(2+) (5 microM) stimulated within 8 min an ERK1/2-activated CFTR-like Cl(-) conductance sensitive to CFTR(inh)-172. Thereafter Cd(2+) induced an apoptotic volume decrease (AVD) within 6 h followed by caspase-3 activation and apoptosis. The early increase in CFTR conductance was followed by the activation of volume-sensitive outwardly rectifying (VSOR) Cl(-) and TASK2 K(+) conductances. By contrast, cftr(-/-) cells exposed to Cd(2+) were unable to develop VSOR currents, caspase-3 activity, and AVD process and underwent necrosis. Moreover in cftr(+/+) cells, Cd(2+) enhanced reactive oxygen species (ROS) production and induced a 50% decrease in total glutathione content (major ROS scavenger in PCT). ROS generation and glutathione decrease depended on the presence of CFTR, since they did not occur in the presence of CFTR(inh)-172 or in cftr(-/-) cells. Additionally, Cd(2+) exposure accelerates effluxes of fluorescent glutathione S-conjugate in cftr(+/+) cells. Our data suggest that CFTR could modulate ROS levels to ensure apoptosis during Cd(2+) exposure by modulating the intracellular content of glutathione.
authors.affiliation: CNRS FRE 3093, Université de Nice-Sophia Antipolis, Nice Cedex 2, France.
authors.forename: Sebastien
authors.initials: S
authors.lastname: L'hoste
authors.forename: Abderrahmen
authors.initials: A
authors.lastname: Chargui
authors.forename: Radia
authors.initials: R
authors.lastname: Belfodil
authors.forename: Christophe
authors.initials: C
authors.lastname: Duranton
authors.forename: Isabelle
authors.initials: I
authors.lastname: Rubera
authors.forename: Baharia
authors.initials: B
authors.lastname: Mograbi
authors.forename: Chantal
authors.initials: C
authors.lastname: Poujeol
authors.forename: Michel
authors.initials: M
authors.lastname: Tauc
authors.forename: Philippe
authors.initials: P
authors.lastname: Poujeol
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001565:Benzoates / Q000494:pharmacology; D002104:Cadmium / Q000633:toxicity; D053148:Caspase 3 / Q000378:metabolism; D018929:Cell Culture Techniques; D002461:Cell Line, Transformed; D048429:Cell Size; D003550:Cystic Fibrosis / Q000473:pathology / Q000503:physiopathology*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000502:physiology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism*; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D018181:Mice, Inbred CFTR; D018408:Patch-Clamp Techniques; D024683:Potassium Channels, Tandem Pore Domain / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D053778:Thiazolidines / Q000494:pharmacology
chemical_list: C482900:3-((3-trifluoromethyl)phenyl)-5-((3-carboxyphenyl)methylene)-2-thioxo-4-thiazolidinone; D001565:Benzoates; C498739:Kcnk5 protein, mouse; D024683:Potassium Channels, Tandem Pore Domain; D017382:Reactive Oxygen Species; D053778:Thiazolidines; D002104:Cadmium; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D048049:Extracellular Signal-Regulated MAP Kinases; D053148:Caspase 3; D005978:Glutathione