Synthesis Of Erythropoietin

The primary site of EPO production in adults is the kidney, and peritubular cells are thought to be responsible for EPO synthesis (20-22). The liver is a secondary site of EPO production, with synthesis occurring in both hepatocyes and fibroblastoid interstitial cells (23). Recently, astrocytes and neurons within the central nervous system have been reported to express EPO (24). No preformed stores of EPO exist, and plasma EPO concentrations are maintained at a constant concentration by basal production of the hormone (25). Within a healthy individual, the plasma EPO concentration tends to be controlled tightly, but there is large interindividual variability (approximately normal range: 4-30 mU/mL). Plasma EPO concentrations have shown a small diurnal variation in some studies but not in others (26,27).

Tissue hypoxia is a physiologic stimulus for EPO production, and numerous studies have shown an exponential increase in plasma EPO with increasing degrees of anemia (1,20). Anemia (hematocrit < 35%) and, as a consequence, tissue hypoxia regulate EPO expression at the gene level, and EPO concentrations can increase 100-1000-fold in response to anemia. The mechanism of hypoxic stimulation of EPO production is the focus of much investigation (22,28). Under conditions of hypoxia, EPO gene transcription is activated when hypoxia-inducible factor-1 (HIF-1) binds to a hypoxia-responsive enhancer located in the 3' flanking sequence of the EPO gene. HIF-1 is a heterodimer composed of an oxygen-sensitive HIF-1 a and a constitutive HIF-1 P (29). This protein complex, in conjunction with other factors, signals EPO gene synthesis. The mechanism by which HIF-1 a activity is regulated by oxygen is partially understood. HIF-1 a contains proline residues within oxygen-dependent domains (ODDs) (30) that are hydroxy-lated by a family of prolyl hydroxylases (HIF-PH1, HIF-PH2, HIF-PH3, and HIF-PH4) (31,32). HIF-PHs are iron-containing proteins that are positively regulated by oxygen. Under conditions of normoxia, HIF-PHs are active, which then hydroxylates HIF-1 a. Hydroxylated HIF-1 a is then targeted for destruction by the von Hippel Lindau tumor suppressor gene (pVHL), a component of protein ubiquitin ligase (33). HIF-1 a is also hydroxylated at an asparagine residue near its C-terminus by another oxygen-regulated hydroxylase, factor inhibiting HIF-1 (FIH) (34,35). Hydroxylation of HIF-1 a by FIH results in inhibition of HIF-1 association with a cofactor (p300) required for transcriptional activation of the EPO gene promoter. Under hypoxic conditions, HIF-PH and FIH are both inactive, allowing for increased levels of active HIF-1 a/HIF-1p/p300 EPO gene transcription complexes and thereby resulting in increased EPO gene transcription.

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