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The Journal of Neuroscience, June 23, 2004, 24(25):5651-5658; doi:10.1523/JNEUROSCI.1288-04.2004
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Neurobiology of Disease
Constitutive Overexpression of Human Erythropoietin Protects the Mouse Retina against Induced But Not Inherited Retinal Degeneration
Christian Grimm,1 Andreas Wenzel,1 Dinu Stanescu,1 Marijana Samardzija,1 Svenja Hotop,1 Mathias Groszer,2 Muna Naash,3 Max Gassmann,4 andCharlotte Remé1 1Laboratory for Retinal Cell Biology, University Eye Hospital, CH-8091 Zurich, Switzerland, 2Howard Hughes Medical Institute, University of California Los Angeles, Los Angeles, California 90095, 3Department of Cell Biology, University of Oklahoma, Oklahoma City, Oklahoma 73104, and 4Institute of Veterinary Physiology, University of Zurich, CH-8091 Zurich, Switzerland
Elevation of erythropoietin (Epo) concentrations by hypoxic preconditioning or application of recombinant human Epo (huEpo) protects the mouse retina against light-induced degeneration by inhibiting photoreceptor cell apoptosis. Because photoreceptor apoptosis is also the common path to cell loss in retinal dystrophies such as retinitis pigmentosa (RP), we tested whether high levels of huEpo would reduce apoptotic cell death in two mouse models of human RP. We combined the two respective mutant mouse lines with a transgenic line (tg6) that constitutively overexpresses huEpo mainly in neural tissues. Transgenic expression of huEpo caused constitutively high levels of Epo in the retina and protected photoreceptors against light-induced degeneration; however, the presence of high levels of huEpo did not affect the course or the extent of retinal degeneration in a light-independent (rd1) and a light-accelerated (VPP) mouse model of RP. Similarly, repetitive intraperitoneal injections of recombinant huEpo did not protect the retina in the rd1 and the VPP mouse. Lack of neuroprotection by Epo in the two models of inherited retinal degeneration was not caused by adaptational downregulation of Epo receptor. Our results suggest that apoptotic mechanisms during acute, light-induced photoreceptor cell death differ from those in genetically based retinal degeneration. Therapeutic intervention with cell death in inherited retinal degeneration may therefore require different drugs and treatments.
Key words: retinal degeneration; erythropoietin; apoptosis; neuroprotection; photoreceptor; transgene
Received Dec 5, 2003; accepted April 29, 2004.
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