Nature Medicine8, 718 - 724 (2002)
Published online: 17 June 2002; | doi:10.1038/nm723
HIF-1-induced erythropoietin in the hypoxic retina protects against light-induced retinal degeneration
Christian Grimm1, Andreas Wenzel1, 6, Matthias Groszer2, 6, Helmut Mayser3, Mathias Seeliger3, Marijana Samardzija1, Christian Bauer4, Max Gassmann4, 5, 6
& Charlotte E. Remé1, 6
1
Retinal Cell Biology, Department of Ophthalmology, University Hospital, Zurich, Switzerland
2
Howard Hughes Medical Institute, University of California Los Angeles, Los Angeles, California, USA
3
Retinal Electrodiagnostic Research Group, Department of Ophthalmology, University of Tuebingen, Tuebingen, Germany
4
Institute of Physiology, University of Zurich, Zurich, Switzerland
5
Institute of Veterinary Physiology, University of Zurich, Zurich, Switzerland
6
A.W. and M. Groszer as second authors, and M. Gassman and C.E.R. as senior authors contributed equally to this study.
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-1 (HIF-1) 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.
(HIF-1
