Molecular Biology of Erythropoietin

Abstract

The glycoprotein hormone erythropoietin (EPO) is an essential viability and growth factor for the erythrocytic progenitors. EPO is mainly produced in the kidneys. EPO gene expression is induced by hypoxia-inducible transcription factors (HIF). The principal representative of the HIF-family (HIF-1, -2 and -3) is HIF-1, which is composed of an O2-labile alpha-subunit and a constant nuclear beta-subunit. In normoxia, the alpha-subunit of HIF is inactivated following prolyl- and asparaginyl-hydroxylation by means of alpha-oxoglutarate and Fe(2+)-dependent HIF specific dioxygenases. While HIF-1 and HIF-2 activate the EPO gene, HIF-3, GATA-2 and NFkappaB are likely inhibitors of EPO gene transcription. EPO signalling involves tyrosine phosphorylation of the homodimeric EPO receptor and subsequent activation of intracellular antiapoptotic proteins, kinases and transcription factors. Lack of EPO leads to anemia. Treatment with recombinant human EPO (rHuEPO) is efficient and safe in improving the management of the anemia associated with chronic renal failure. RHuEPO analogues with prolonged survival in circulation have been developed. Whether the recent demonstration of EPO receptors in various non-hemopoietic tissues, including tumor cells, is welcome or ominous still needs to be clarified. Evidence suggests that rHuEPO may be a useful neuroprotective agent.

Erythropoietin improves functional and histological recovery of traumatized skeletal muscle tissue

“…Recently, EPO has also been recognized as anti-apoptotic and tissueprotective pleiotropic viability and growth factor in nonvarious nonhemopoietic tissues. [6][7][8] Therefore, we hypothesized that EPO may improve regeneration and functionality of the skeletal muscle after a blunt crush injury, most supposedly by its multiple salutary effects on cell proliferation, tissue integrity and microcirculation.…”

Prevalence of Iron Deficiency Anemia in Patients with Chronic Heart Failure

“…Erythropoietin, a 30.4 -kDa glycoprotein growth factor generated primarily by kidney, is the crucial ingredient of the homeostatic system for regulation of red blood cell mass and tissue oxygen delivery. [16][17][18][19] Erythropoietin prevents the programmed cell death of erythrocyte progenitor cells and thereby stimulates their proliferation, maturation, and terminal differentiation. [18] Any irregularity that reduces renal secretion of or bone marrow response to erythropoietin may end in anemia.…”

“…[16][17][18][19] Erythropoietin prevents the programmed cell death of erythrocyte progenitor cells and thereby stimulates their proliferation, maturation, and terminal differentiation. [18] Any irregularity that reduces renal secretion of or bone marrow response to erythropoietin may end in anemia. Iron deficiency is present in <30% of anemic patients with CHF, so the preponderance of observed anemia is normocytic, often classified as anemia of chronic disease.…”

Multiple roles of hypoxia in ovarian function: roles of hypoxia-inducible factor-related and -unrelated signals during the luteal phase

“…In kidney and liver, hypoxia induces the synthesis of EPO (Semenza and Wang 1992;Beck et al 1993), which stimulates erythropoiesis, thereby increasing the O2 capacity in the blood (Jelkmann 2004). In virtually all tissues, hypoxia induces the synthesis of proteins controlling local blood flow, such as VEGF (Forsythe et al 1996;Kimura et al 2001), endothelial nitric oxide synthase (eNOS) (Coulet et al 2003), and heme oxygenase-1 (HOX-1) (Lee et al 1997).…”