HIF-1-induced erythropoietin in the hypoxic retina protects against light-induced retinal degeneration.
Erythropoietin (Epo) is upregulated by hypoxia and provides protection against apoptosis of erythroid progenitors in bone marrow and brain neurons. Here we show in the adult mouse retina that acute hypoxia dose-dependently stimulates expression of Epo, fibroblast growth factor 2 and vascular endothelial growth factor via hypoxia-inducible factor-1alpha (HIF-1alpha) stabilization. Hypoxic preconditioning protects retinal morphology and function against light-induced apoptosis by interfering with caspase-1 activation, a downstream event in the intracellular death cascade. In contrast, induction of activator protein-1, an early event in the light-stressed retina, is not affected by hypoxia. The Epo receptor required for Epo signaling localizes to photoreceptor cells. The protective effect of hypoxic preconditioning is mimicked by systemically applied Epo that crosses the blood retina barrier and prevents apoptosis even when given therapeutically after light insult. Application of Epo may, through the inhibition of apoptosis, be beneficial for the treatment of different forms of retinal disease.
Grimm
Christian
C
Retinal Cell Biology, Department of Ophthalmology, University Hospital, Zurich, Switzerland. cgrimm@opht.unizh.ch
Wenzel
Andreas
A
Groszer
Matthias
M
Mayser
Helmut
H
Seeliger
Mathias
M
Samardzija
Marijana
M
Bauer
Christian
C
Gassmann
Max
M
Remé
Charlotte E
CE
D000818:Animals; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004596:Electroretinography; D016228:Endothelial Growth Factors / Q000235:genetics; D004921:Erythropoietin / Q000096:biosynthesis / Q000235:genetics*; D016222:Fibroblast Growth Factor 2 / Q000235:genetics; D006801:Humans; D000860:Hypoxia / Q000503:physiopathology; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008027:Light / Q000009:adverse effects*; D008222:Lymphokines / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D009687:Nuclear Proteins / Q000378:metabolism*; D012162:Retinal Degeneration / Q000473:pathology / Q000517:prevention & control*; D014157:Transcription Factors / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D004268:DNA-Binding Proteins; D016228:Endothelial Growth Factors; C497442:HIF1A protein, human; C497443:Hif1a protein, mouse; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008222:Lymphokines; D009687:Nuclear Proteins; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D016222:Fibroblast Growth Factor 2; D004921:Erythropoietin