Biology Reference
In-Depth Information
Control of EPO production and elimination
In the 19th and 20th centuries, researchers used the effects of hypoxia to for-
mulate theories about the existence of EPO. (See Chapter 2 by Foote for fur-
ther information.) EPO is widely recognized as a product of interstitial cells
localized around the proximal tubule of the kidney in the adult [11, 12]; how-
ever, several other quantitatively less-significant sites of production have been
documented including fetal and adult liver [11, 13-16], brain, testis, lung,
spleen, placenta, bone marrow, and ovary [11, 13-23]. Although the precise
nature of the oxygen-sensing mechanism has yet to be defined,the generation
of reactive oxygen intermediates has been suggested as a preliminary step in
upregulating EPO production. In hypoxia, a DNA sequence 3' to the
EPO
gene
is activated by a transcription factor, hypoxia-inducible factor (HIF) that
appears to be responsible for switching several genes regulated by hypoxia,
including EPO [24-26]. In addition to HIF, other signals such as HNF4,
p300/CREB, and the COUP family of transcription factors are known to play
a role in EPO regulation [27, 28]. Post-transcriptional events have also been
reported to be involved [29].
Elimination of both recombinant and endogenous EPO remains somewhat
of a mystery. (See Chapter 6 by Heatherington for more information.) A small
amount of EPO is detected in the urine and a role for erythroid cells in clear-
ance has been suggested [30-32]. Other mechanisms, perhaps involving the
asialoglycoprotein receptor on liver cells have been considered [33]. It is pos-
sible that a combination of clearance pathways, some specific, some non-spe-
cific, some yet to be defined, account for the removal of EPO from the body.
EPO and erythropoiesis
The major function of red blood cells (erythrocytes) is to transport oxygen to
the tissues of the body. The erythrocyte component represents about 40% to
45% of the blood by volume. A normal adult may have 5 L of blood and an
erythrocyte count of 5
10
9
/L. The red cell life-span in such a normal adult is
approximately 100 to 120 days. To maintain a stable number of erythrocytes,
replacing those lost by normal aging alone, requires replacement of 1% ery-
throcytes per day, i.e., production of 2.5
×
10
11
cells per day or more than 10
10
cells per hour. This prodigious rate of production is maintained in most cir-
cumstances for the lifetime of the individual. Thus, erythropoiesis is a highly
dynamic process. EPO has a pivotal role in this process.
As discussed elsewhere in this volume (see Chapter 1 by Israels and
Israels), the cellular target of EPO in erythropoiesis was traditionally referred
to as the erythropoietin responsive cell. This population is now known to rep-
resent progenitor cells in late erythroid burst-forming unit (BFU-E) stage
through the erythroid colony-forming unit (CFU-E) stage and the morpholog-
ically recognizable erythroblasts (Fig. 1 and Chapter 1). EPOR is, however,
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