Glutathione depletion activates mitogen-activated protein kinase (MAPK) pathways that display organ-specific responses and brain protection in mice
Por:
Limón-Pacheco J.H., Hernández N.A., Fanjul-Moles M.L., Gonsebatt M.E.
Publicada:
1 ene 2007
Resumen:
Because mitogen-activated protein kinases (MAPK) are downstream effectors of antioxidant responses, changes in GSH levels in an organism might induce organ-specific responses. To test our hypothesis, mice were treated intraperitoneally with L-buthionine-S-R-sulfoximine (BSO) to inhibit GSH synthesis. A time-related GSH depletion in the liver and kidney correlated with p38MAPK phosphorylation and induction of thioredoxin 1 (Tx-1) transcription. This positive regulation was associated with nuclear translocation of NF-?B and ATF-2 and c-Jun phosphorylation in the liver, but only c-Jun phosphorylation in the kidney. Increased levels of GSH were observed in the brain together with extracellular regulated kinase 2 (ERK2) activation, Nrf2 nuclear accumulation, and increases in transcription of Nrf2, xCT, ?-glutamylcysteine synthetase (?GCSr), and Tx-1. Pretreatment with MAPK inhibitors SB203580 and U0126, or addition of the exogenous thiol N-acetylcysteine, abrogated both p38MAPK and ERK2 activation as well as downstream effects on gene expression. No effect on ?GCSr was observed. These results indicate that in mice, GSH depletion is associated with p38MAPK phosphorylation in the liver and kidney and with ERK2 activation in the brain, in what could be considered part of the brain's protective response to thiol depletion. © 2007 Elsevier B.V. All rights reserved.
Filiaciones:
Limón-Pacheco J.H.:
Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Ciudad Universitaria, Distrito Federal, Mexico
Hernández N.A.:
Subdirección de Investigación Clínica, Instituto Nacional de Cancerología, Av. San Fernando 22, Codigo Postal 14000 Tlalpan, Distrito Federal, Mexico
Fanjul-Moles M.L.:
Laboratorio de Neurobiología, Facultad de Ciencias, Universidad Nacional Autónoma de México, Mexico
Gonsebatt M.E.:
Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Ciudad Universitaria, Distrito Federal, Mexico
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