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insult protects photoreceptors - demonstrating that rEPO, given in high dose
of 5,000 U/kg, crosses the blood-retina barrier [188].
Cell-protective effects of rEPO on neurons of the retina have been found in
a rat model of transient global retinal ischemia induced by raising intraocular
pressure. Acute retinal ischemia followed by reperfusion results in a time-
dependent (maximum at 72 hours), up to four-fold induction of EPOR in the
retina and was identified in murine ganglion cells, amacrine cells, and astro-
cytes [189]. Recombinant EPO reduces the histopathological damage in tran-
sient global ischemia and promotes the functional recovery of the retina if sys-
temically administered in a high dose of 5,000 U/kg, before or immediately
after induction of tissue damage. Data generated with TUNEL staining suggest
that rEPO has cell protective effects by inhibiting apoptosis [189].
These data allow new concepts for rEPO as a potential therapeutic agent for
several retinal diseases including acute glaucoma, acute retinal occlusion, dia-
betic retinopathy, and hypertensive retinopathy. New experimental strategies
are being developed to achieve a local effect of EPO by using an intraocularly
administered, inducible adeno-associated virus (AAV) vector construct [190].
However, angiogenic effects of EPO must be considered, for example in ven-
tilated pre-term babies who may be treated with relatively high doses of rEPO
to prevent transfusions during the anemia of prematurity, but who are at high
risk for retinopathy of prematurity.
Conclusions
The expression and regulation of EPOR in mammalian non-hematopoietic
organs involves developmental-stage and tissue-specific mechanisms. Further
studies are necessary to elucidate these regulatory mechanisms. A more com-
plete understanding of this system might broaden the therapeutic use of rEPO
toward repair of chronically or acutely damaged tissue.
Acknowledgement
I thank Dr. Robert D. Christensen, University of South Florida, St. Petersburg/FL, USA, and Dr.
Joachim Fandrey, University of Essen, Germany, for the critical review and stimulating discussion of
this manuscript. Author's work was partially supported by a grant from the Deutsche
Forschungsgemeinschaft (DA 484/1-1).
References
1 Jacobs K, Shoemaker C, Rudersdorf R, Neill SD, Kaufman RJ, Mufson A, Seehra J, Jones SS,
Hewick R, Fritsch EF et al. (1985) Isolation and characterization of genomic and cDNA clones of
human erythropoietin. Nature 313: 806-810
2Lin FK, Suggs S, Lin CH, Browne JK, Smalling R, Egrie JC, Chen KK, Fox GM, Martin F,
Stabinsky Z et al. (1985) Cloning and expression of the human erythropoietin gene. Proc Natl
Acad Sci USA 82: 7580-7584
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