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M. Samardzija, A. Wenzel, M. Gassmann, C.E. Remé, C. Grimm; Erythropoietin in Inherited Retinal Degenerations in Mice . Invest. Ophthalmol. Vis. Sci. 2003;44(13):2835.
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Purpose: The elevation of endogenous erythropoietin (epo) by hypoxic preconditioning or the application of recombinant epo by intraperitoneal injections rescues photoreceptors from light damage in mice. Here we tested a potential beneficiary effect of high levels of epo on the induction and course of retinal degenerations caused by gene mutations. Methods: A transgenic mouse (tg6) expresses human erythropoietin under control of the PDGF promoter resulting in 19-fold elevated epo levels in serum and 28-fold increased epo levels in brain. This transgene was crossed into a mouse expressing a mutation in the beta subunit of the phosphodiesterase gene (rd/rd). Retinal development and degeneration was monitored morphologically at postnatal day 11, 21 and 37. Expression of the epo transgene and of epo receptor was tested by immunohistochemistry, ELISA and Western blotting. Results: In both, wildtype and rd mouse, the transgene was expressed during development leading to elevated epo levels in the retina. Epo was mainly detected in the outer nuclear layer as well as in the ganglion cell layer. Expression of the epo receptor was similar in wildtype and in the rd mouse at postnatal day 4 and 10, but was lower at day 21 and hardly detectable at day 62 in the rd mouse indicating that the receptor mainly is expressed on photoreceptors which degenerate in the rd mouse. In contrast, levels (per µg retinal protein) of the glial acidic protein (GFAP) were increased in the rd mouse. Despite the presence of the epo transgene, retinal degeneration proceeded similar in wildtype and rd mice. Conclusions: The presence of high levels of epo was not sufficient to rescue photoreceptor degeneration induced by the rd mutation. Since degeneration in the rd mouse coincides with developmental apoptosis, a general epo mediated inhibition of apoptosis may have been prohibited by a mechanism securing normal developmental apoptosis. Currently we are testing the effect of elevated epo levels on retinal degeneration induced by the rds (peripherin) and the VPP (rhodopsin) mutations. In both models, retinal degeneration starts at a later timepoint, not interferring with developmental apoptosis.
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