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FASEB J. 2018 May;32(5):2438-2451. doi: 10.1096/fj.201700985R. Epub 2018 Jan 8.

HIF-1α stabilization reduces retinal degeneration in a mouse model of retinitis pigmentosa.

Author information

1
Grupo de Investigación en Biomedicina Molecular, Celular y Genómica, Instituto de Investigación Sanitaria La Fe, Valencia, Spain.
2
Centros de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.
3
Unidad de Data Science, Bioestadística y Bioinformática, Instituto de Investigación Sanitaria La Fe, Valencia, Spain; and.
4
Unidad de Genética, Hospital Universitario y Politécnico La Fe, Valencia, Spain.

Abstract

Retinitis pigmentosa (RP) is a group of inherited retinal dystrophies characterized by progressive and irreversible loss of vision due to rod and cone degeneration. Evidence suggests that an inappropriate oxygen level could contribute to its pathogenesis. Rod cell death could increase oxygen concentration, reduce hypoxia-inducible factor 1 (HIF-1α) and contribute to cone cell death. The purposes of this study were: 1) to analyze the temporal profile of HIF-1α, its downstream effectors VEGF, endothelin-1 (ET-1), iNOS, and glucose transporter 1 (GLUT1), and neuroinflammation in retinas of the murine model of rd10 ( retinal degeneration 10) mice with RP; 2) to study oxygen bioavailability in these retinas; and 3) to investigate how stabilizing HIF-1α proteins with dimethyloxaloglycine (DMOG), a prolyl hydroxylase inhibitor, affects retinal degeneration, neuroinflammation, and antioxidant response in rd10 mice. A generalized down-regulation of HIF-1α and its downstream targets was detected in parallel with reactive gliosis, suggesting high oxygen levels during retinal degeneration. At postnatal d 18, DMOG treatment reduced photoreceptor cell death and glial activation. In summary, retinas of rd10 mice seem to be exposed to a hyperoxic environment even at early stages of degeneration. HIF-1α stabilization could have a temporal neuroprotective effect on photoreceptor cell survival, glial activation, and antioxidant response at early stages of RP.-Olivares-González, L., Martínez-Fernández de la Cámara, C., Hervás, D., Millán, J. M., Rodrigo, R. HIF-1α stabilization reduces retinal degeneration in a mouse model of retinitis pigmentosa.

KEYWORDS:

DMOG; hyperoxia; inflammation; oxidative damage; reactive gliosis

PMID:
29295858
DOI:
10.1096/fj.201700985R

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