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senescence, new red cells must be continuously produced in order
to maintain an optimum erythrocyte mass, but these express the
EPO receptor only transiently. Therefore, EPO concentrations
within the circulation are not episodic, but rather are sustained.
The plasma half life of EPO made by the kidney is correspondingly
prolonged (~4-6 h), due to the presence of four oligosaccharide
chains capped by terminal sialic acids.
2
Tissue Protection
In the 1990s it was discovered that tissues other than the kidney
(as well as the liver and spleen in some species and in neonates) can
synthesize EPO and further, that non-hematopoietic tissues (e.g.,
the brain (
2
) and kidney (
3
)) can express a receptor for EPO.
Results of the earliest work indicated that hypoxia was a potent
stimulus of EPO production in the brain, e.g., by astrocytes (
4
),
and further, endogenous EPO or recombinant EPO administered
locally was neuroprotective (
5
). However, the EPO molecule pro-
duced for neuroprotection by astrocytes was found to be smaller
than renal EPO, having less fully sialyted oligosaccharide chains
(hypoglycosylated EPO; hypoEPO) (
4
). This structural feature
results in a much shorter serum half-life of hypoEPO than for renal
EPO. The hypoEPO variant may have evolved to limit cross-talk
between the tissue protective system and the hematopoietic
system.
Work performed in the nervous system showed that unlike
hematopoiesis, which required constant stimulation by EPO to be
effective, neuroprotection by EPO required only a brief exposure.
Specifically, using an in vitro system of neuronal injury, it was
shown that if injured cells which were programmed for apoptosis
were exposed to renal EPO, programmed cell death was effectively
prevented. The required duration of exposure to EPO, however,
was surprisingly very short: only 5 min produced a degree of neu-
roprotection equivalent to a continued presence. Further, this neu-
roprotection required upon gene expression, as interference with
RNA synthesis abolished the neuroprotective effects observed (
5
).
Similar to the mechanism of action of EPO in the hematopoietic
system, hypoEPO operates a molecular switch, turning on long-
lasting biological actions.
At the time of the initial discoveries of EPO's protective role in
tissue injury, it was thought that such a large protein could not
cross the blood brain barrier. But, in fact, peripherally administered
EPO was highly effective in protecting against not only hypoxic
injury, but also other forms of damage, including blunt trauma,
excessive stimulation by excitotoxins, and immune-mediated dis-
ease (
6
). Notably, however, doses substantially higher than those
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