Erythropoietin Gene Expression: Developmental-Stage Specificity, Cell-Type Specificity, and Hypoxia Inducibility

Abstract

Erythrocytes play an essential role in the delivery of oxygen from the lung to every organ; a decrease in erythrocytes (anemia) causes hypoxic stress and tissue damage. To maintain oxygen homeostasis in adult mammals, when the kidney senses hypoxia, it secretes an erythroid growth factor, erythropoietin (Epo), which stimulates erythropoiesis in the bone marrow. Recently, studies using genetically modified mice have shown that the in vivo expression profile of the Epo gene changes dramatically during development. The first Epo-producing cells emerge in the neural crest and neuroepithelium of mid-stage embryos and support primitive erythropoiesis in the yolk sac. Subsequently, Epo from the hepatocytes stimulates erythropoiesis in the fetal liver of later stage embryos in a paracrine manner. In fact, erythroid lineage cells comprise the largest cell population in the fetal liver, and hepatocytes are distributed among the erythroid cell clusters. Adult erythropoiesis in the bone marrow requires Epo that is secreted by renal Epo-producing cells (REP cells). REP cells are widely distributed in the renal cortex and outer medulla. Hypoxia-inducible Epo production both in hepatocytes and REP cells is controlled at the gene transcription level that is mainly mediated by the hypoxia-inducible transcription factor (HIF) pathway. These mouse studies further provide insights into the molecular mechanisms of the cell-type specific, hypoxia-inducible expression of the Epo gene, which involves multiple sets of cis-and trans-regulatory elements.

Maternal nutrient restriction in guinea pigs leads to fetal growth restriction with evidence for chronic hypoxia

“…HP-1 staining in the liver was widely seen within the hepatocytes, while in the kidney this was considerably less in the glomeruli than in the surrounding proximal convoluted tubule area. This is consistent with renal blood flow initially to the glomeruli, and thereby better oxygenation, prior to passing through the surrounding cortical tissue as reported for the adult kidney (27). HP-1 was substantially increased in the liver and kidney cortical tissues of both male and female FGR-MNR fetuses, indicating lower levels of oxygenation in these tissues relative to those of the respective AGA-Control fetuses.…”

“…EPO synthesis is inversely related to oxygen availability in tissues, with the main determinant being the transcriptional activity of its gene by hypoxia-inducible factor 1 (HIF-1) (19,24). During fetal development, EPO synthesis gradually changes from hepatocytes stimulating erythropoiesis in the liver to renal EPOproducing cells in the cortex and outer medulla stimulating erythropoiesis in the bone marrow, with the timing for this transition being species dependent (25)(26)(27). However, secretion of small amounts of EPO has also been identified in other fetal tissues, and for the placenta this can become substantial in response to fetal hypoxemia (25,26).…”

Comparative analysis of tissue expression and methylation reveal the crucial hypoxia genes in hypoxia resistant animals

“…It is well known that EPO plays an essential role in the delivery of oxygen from the lung to every organ, and increased response to hypoxia (Suzuki 2015). Besides, independent of hematopoietic activity, administration of EPO improves cardiac contractility in post-hypoxic mice (Sterin-Borda et al 2003), represses cell death of the myocardium in a rabbit AMI model (Parsa et al 2003), and is a promising treatment for acute myocardial infarction (Ozawa et al 2010).…”

Erythropoietin between therapy and doping : Two sides of the same coin

“…The amount of erythropoietin produced by the liver is inadequate for organism needs (20). Uremic toxins, deficiency of vitamin D, B 12 , folate and iron, inflammation, shorter erythrocytes lifespan, gastrointestinal bleedings, also contribute to anaemia development (19,21). Anaemia can occur already with decline of glomerular filtration rate to 40-50 ml/min (20).…”

“…Molecules of EPO bind to the EPO receptors, type 1 transmembrane proteins belonging to hematopoietic cytokine receptor superfamily, which are Janus tyrosine kinase 2 (JAK2) dependent, and undergo dimerization in response to EPO binding (1,2). This is followed by activation of several signaling pathways, mostly JAK2/STAT5 pathway, and PI3K/Akt, but also by other signal molecules like MAP kinase, ERK1/2, protein kinase C and heat shock proteins (11,12). Cytoplasmic protein hematopoietic cell phosphatase (HCP) terminates signal transduction (9).…”