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HIF-1-induced erythropoietin in the hypoxic retina protects against light-induced retinal degeneration

Nature Medicine volume 8, pages 718–724 (2002)Cite this article

Abstract

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-1α (HIF-1α) 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.

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Figure 1: Hypoxia protects retinal morphology and function after light insult (5,800 lx).
Figure 2: Hypoxic preconditioning interferes with a late step in the apoptotic signaling cascade.
Figure 3: Hypoxic exposure induces HIF-1α, VEGF, Epo and FGF-2 in a dose- and time-dependent manner.
Figure 4: EpoR (red staining) localizes to inner segments of photoreceptors and to the region of synaptic complexes in the outer plexiform layer.
Figure 5: Systemic administration of hrEpo protects photoreceptors against light damage.
Figure 6: Intracellular signaling molecules after hypoxic preconditioning and light exposure.

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Acknowledgements

We thank D. Greuter, G. Hoegger, C. Imsand and S. Keller for technical assistance; I. Desbaillets for discussion; F. Valeri for statistical analysis; U. Busse for administrative help; and T. Seiler and K. Landau for continuous support of our work. This study was supported by the Swiss National Science Foundation, Theodore Ott Foundation Switzerland, Hartmann-Müller Foundation Switzerland, Velux Foundation, Switzerland and the German Research Council.

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Author notes

  1. Andreas Wenzel, Matthias Groszer, Max Gassmann and Charlotte E. Remé: A.W. and M. Groszer as second authors, and M. Gassman and C.E.R. as senior authors contributed equally to this study.

Authors and Affiliations

  1. Department of Ophthalmology, Retinal Cell Biology, University Hospital, Zurich, Switzerland

    Christian Grimm, Andreas Wenzel, Marijana Samardzija & Charlotte E. Remé

  2. Howard Hughes Medical Institute, University of California Los Angeles, Los Angeles, California, USA

    Matthias Groszer

  3. Department of Ophthalmology, Retinal Electrodiagnostic Research Group, University of Tuebingen, Tuebingen, Germany

    Helmut Mayser & Mathias Seeliger

  4. Institute of Physiology, University of Zurich, Zurich, Switzerland

    Christian Bauer & Max Gassmann

  5. Institute of Veterinary Physiology, University of Zurich, Zurich, Switzerland

    Max Gassmann

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Correspondence to Christian Grimm.

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Grimm, C., Wenzel, A., Groszer, M. et al. HIF-1-induced erythropoietin in the hypoxic retina protects against light-induced retinal degeneration. Nat Med 8, 718–724 (2002). https://doi.org/10.1038/nm723

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