PGC-1α signaling coordinates susceptibility to metabolic and oxidative injury in the inner retina.
Am J Pathol
; 184(4): 1017-1029, 2014 Apr.
Article
em En
| MEDLINE
| ID: mdl-24508229
ABSTRACT
Retinal ganglion cells (RGCs), used as a common model of central nervous system injury, are particularly vulnerable to metabolic and oxidative damage. However, molecular mechanisms underlying this sensitivity have not been determined in vivo. PGC-1α (encoded by PPARGC1A) regulates adaptive metabolism and oxidative stress responses in a tissue- and cell-specific manner. Aberrant PGC-1α signaling is implicated in neurodegeneration, but the mechanism underlying its role in central nervous system injury remains unclear. We provide evidence from a mouse model that PGC-1α expression and activity are induced in adult retina in response to metabolic and oxidative challenge. Deletion of Ppargc1a dramatically increased RGC loss, in association with dysregulated expression of PGC-1α target metabolic and oxidative stress response genes, including Hmox1 (encoding HO-1), Tfam, and Vegfa. Vehicle-treated and naive Ppargc1a(-/-) mice also showed mild RGC loss, and surprisingly prominent and consistent retinal astrocyte reactivity. These cells critically regulate metabolic homeostasis in the inner retina. We show that PGC-1α signaling (not previously studied in glia) regulates detoxifying astrocyte responses to hypoxic and oxidative stresses. Finally, PGC-1α expression was modulated in the inner retina with age and in a model of chronic optic neuropathy. These data implicate PGC-1α signaling as an important regulator of astrocyte reactivity and RGC homeostasis to coordinate pathogenic susceptibility to metabolic and oxidative injury in the inner retina.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Células Ganglionares da Retina
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Transdução de Sinais
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Estresse Oxidativo
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article