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Erythropoietin

Roland H. Wenger, Armin Kurtz

10.1002/cphy.c100075

Source: Volume 1, Issue 4, October 2011

Published online: October 2011

Full Article on Wiley Online Library



Abstract

The hormone erythropoietin (Epo) is the main humoral regulator of erythropoiesis. It binds to specific receptors belonging to the cytokine receptor superfamily. Epo stimulates proliferation and differentiation of erythroid precursor cells, but may also bind to and exert some additional effects in nonhemopoietic tissues. It is mainly produced in the kidneys and to minor extents also in the liver and in the brain. The plasma concentration of erthyropoietin is inversely related to the oxygen content of the blood. The secretion of Epo into the circulation and hence its plasma concentrations are mainly determined by the transcription rate of the Epo gene, which itself is essentially under control of the cellular oxygen concentration. Sinks of the oxygen concentrations increase the activity of the hypoxia‐inducible transcription factor (HIF), which in turn triggers Epo gene transcription. Disorders of kidney function lead to inappropriate Epo production, what may result in anemia or polycythemia. © 2011 American Physiological Society. Compr Physiol 1:1759‐1794, 2011.

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Figure 1. Figure 1.

Three‐dimensional structure of the human erythropoietin molecule. Left panel: three‐dimensional solution structure of human Epo as determined by nuclear magnetic resonance spectroscopy. Structural data were taken from the Protein Databank (http://www.rcsb.org/pdb; PDB ID: 1BUY) and displayed using the Cn3D viewer (http://www.ncbi.nlm.nih.gov/Structure/CN3D/cn3d.shtml).
Figure 2. Figure 2.

Organization of the erythropoietin (Epo) gene. The Epo gene is schematically illustrated with 5′‐ untranslated, exons and 3′‐untranslated regions. During hypoxia, the hypoxia‐inducible transcription factor (HIF)‐α/β heterodimer is stabilized and binds to a site on the 3′‐enhancer. Downstream of this site, the nuclear receptor hepatocyte nuclear factor‐4 binds constitutively to the tandem‐repeat hormone response elements and also to the α‐subunit of HIF. Both HIF‐subunits bind to the transcriptional activator p300, providing a mechanism for triggering the Epo gene promoter to transcribe the mRNA. Between the HIF1 and HRE binding sites, an essential sequence with an as yet unknown mechanism of operation is located.
Figure 3. Figure 3.

Stimulation of erythropoiesis by Epo. Colony‐forming unit (CFU)‐granulocyte‐erythrocyte‐monocyte‐megakaryocyte (GEMM) myeloid stem cells differentiate into burst‐forming unit erythroid (BFU‐E) cells that differentiate further into CFU erythroid (CFU‐E) cells. Erythroid colony formation at this stage is Epo‐dependent. The first morphologically distinguishable cells of the erythroid lineage, the proerythroblasts, respond to Epo by increased hemoglobin synthesis. Differentiation downstream of the erythroblast stage, enucleation, intravasation, and final maturation to erythrocytes is independent of Epo.
Figure 4. Figure 4.

Relationship between hematocrit and plasma erythropoietin in rats. Anemia was induced by various maneuvers as indicated.

[Modified, with permission, from ref. 265.]
Figure 5. Figure 5.

Relationship between serum immunoreactive (ir) EPO levels and hemoglobin concentration in patients with hypo‐ and hyperregenerative nonrenal anemias (black triangles) and in patients with chronic renal failure (white triangles) (excluding patients with polycystic kidney disease). The rectangle depicts the interquartile range (dark stippled) and 95% confidence range of EPO levels in nonanemic healthy adults. [Adapted, with permission, from 250.]
Figure 6. Figure 6.

Erythropoietin receptor signaling. Binding of Epo to the Epo‐R initiates auto‐ or trans‐phosphorylation of the Janus kinase (JAK) family. JAK2 then phosphorylates several tyrosine residues of the Epo‐R intracellular domain, creating docking sites for the SH2 domains of several signal transduction proteins, including STAT5. Once bound to the Epo‐R, STAT5 and other signaling proteins become phosphorylated and activated. Phosphorylated STAT5 dissociates from the receptor, homodimerizes, moves to the nucleus, and activates gene expression.
Figure 7. Figure 7.

Upper panel: Localization of erythropoietin (Epo)‐producing cells in the kidney. Combined in situ hybridization and immunohistochemistry on the same tissue section taken from anemic rat renal cortex. Left: Demonstration of Epo mRNA. Right: Double‐labeling on the same tissue section with antibody to 5‐ectonucleotidase. Cells positively stained with either technique are indicated by arrowheads. Only a minor proportion of 5′‐ectonucleotidase‐positive interstitial cells reveal Epo mRNA expression. Double‐labeled cells typically lie in angles between adjacent tubules, or between vessels and tubules. (Magnification × 800.)

(Courtesy of S. Bachmann, Berlin.) Lower panel: Topography of the production of Epo in the rat kidney. Left: The cortical labyrinth is well visualized using an enzyme histochemical technique for 5″‐nucleotidase, with the strong reaction seen as black deposits in the proximal convoluted tubule and in the fibroblasts. Right: In situ hybridization of Epo‐mRNA in the kidney of an anemic rat. The comparison of the two micrographs shows that hybridization took place in the cortical labyrinth (delimited with a dotted line), but not in the medullary rays or in the outer medulla. (Magnification: A ∼ ×62, B ∼ ×95.) [Reproduced, with permission, from ref. 265.]
Figure 8. Figure 8.

Temporal pattern of plasma EPO concentrations during acute hypoxia. Time‐dependent change in serum immunoreactive erythropoietin (Epo) in rats exposed to an inspiratory oxygen tension of 60 mmHg in a normobaric atmosphere. Total gas pressure was kept constant by balance nitrogen. Plasma Epo levels start to increase after a delay phase (1), then increase linearly (phase 2) to reach peak values (phase 3). Then Epo levels decline (phase 4) to reach a stable steady‐state level (phase 5).
Figure 9. Figure 9.

Oxygen dependency of EPO plasma peak concentrations. Peak concentrations of plasma Epo concentration in rats exposed to different inspiratory oxygen tensions for two days.
Figure 10. Figure 10.

Oxygen dependency of the number of erythropoietin (Epo)‐expressing cells in rat kidney cortex. Relationship between the number of Epo producing cells per square centimeter of renal cortex and the inspiratory oxygen tension in rats.
Figure 11. Figure 11.

Oxygen dependency of erythropoietin mRNA in primary cultured rat hepatocytes. Freshly isolated rat hepatocytes were plated on gas permeable culture supports and were exposed to different oxygen concentration in a normobaric atmosphere for 3 h.
Figure 12. Figure 12.

Oxygen sensing and Epo gene regulation. HIFα protein stability and transcriptional activity are regulated by PHD prolyl and FIH asparagine hydroxylases, respectively. This reaction needs oxygen, vitamin C, Fe(II) and 2‐oxoglutarate and is inhibited by succinate, fumarate, and reactive oxygen species (ROS). Upon stabilization, HIF‐2α translocates to the nucleus, heterodimerizes with HIFβ and transactivates the Epo gene.
Figure 13. Figure 13.

Chemical reaction scheme of HIFα prolyl‐4‐hydroxylase domain (PHD) enzymes. Prolyl residues of HIFα are hydroxylated by PHDs at the fourth carbon atom in an oxidative decarboxylation reaction that needs oxygen and 2‐oxoglutarate as co‐substrates, and ascorbate and Fe(II) as co‐factors. Succinate and CO2 are produced as co‐products. The reaction is inhibited by hypoxia, iron chelation, transition metals such as cobalt, nickel and manganese, as well as by an excess of 2‐oxoglutarate analogues such as 2‐oxalylglycine or its cell‐permeable ester dimethyloxalylglycine (DMOG).
Figure 14. Figure 14.

Renal oxygen sensing controlling the production of Epo.


Figure 1.

Three‐dimensional structure of the human erythropoietin molecule. Left panel: three‐dimensional solution structure of human Epo as determined by nuclear magnetic resonance spectroscopy. Structural data were taken from the Protein Databank (http://www.rcsb.org/pdb; PDB ID: 1BUY) and displayed using the Cn3D viewer (http://www.ncbi.nlm.nih.gov/Structure/CN3D/cn3d.shtml).



Figure 2.

Organization of the erythropoietin (Epo) gene. The Epo gene is schematically illustrated with 5′‐ untranslated, exons and 3′‐untranslated regions. During hypoxia, the hypoxia‐inducible transcription factor (HIF)‐α/β heterodimer is stabilized and binds to a site on the 3′‐enhancer. Downstream of this site, the nuclear receptor hepatocyte nuclear factor‐4 binds constitutively to the tandem‐repeat hormone response elements and also to the α‐subunit of HIF. Both HIF‐subunits bind to the transcriptional activator p300, providing a mechanism for triggering the Epo gene promoter to transcribe the mRNA. Between the HIF1 and HRE binding sites, an essential sequence with an as yet unknown mechanism of operation is located.



Figure 3.

Stimulation of erythropoiesis by Epo. Colony‐forming unit (CFU)‐granulocyte‐erythrocyte‐monocyte‐megakaryocyte (GEMM) myeloid stem cells differentiate into burst‐forming unit erythroid (BFU‐E) cells that differentiate further into CFU erythroid (CFU‐E) cells. Erythroid colony formation at this stage is Epo‐dependent. The first morphologically distinguishable cells of the erythroid lineage, the proerythroblasts, respond to Epo by increased hemoglobin synthesis. Differentiation downstream of the erythroblast stage, enucleation, intravasation, and final maturation to erythrocytes is independent of Epo.



Figure 4.

Relationship between hematocrit and plasma erythropoietin in rats. Anemia was induced by various maneuvers as indicated.

[Modified, with permission, from ref. 265.]


Figure 5.

Relationship between serum immunoreactive (ir) EPO levels and hemoglobin concentration in patients with hypo‐ and hyperregenerative nonrenal anemias (black triangles) and in patients with chronic renal failure (white triangles) (excluding patients with polycystic kidney disease). The rectangle depicts the interquartile range (dark stippled) and 95% confidence range of EPO levels in nonanemic healthy adults. [Adapted, with permission, from 250.]



Figure 6.

Erythropoietin receptor signaling. Binding of Epo to the Epo‐R initiates auto‐ or trans‐phosphorylation of the Janus kinase (JAK) family. JAK2 then phosphorylates several tyrosine residues of the Epo‐R intracellular domain, creating docking sites for the SH2 domains of several signal transduction proteins, including STAT5. Once bound to the Epo‐R, STAT5 and other signaling proteins become phosphorylated and activated. Phosphorylated STAT5 dissociates from the receptor, homodimerizes, moves to the nucleus, and activates gene expression.



Figure 7.

Upper panel: Localization of erythropoietin (Epo)‐producing cells in the kidney. Combined in situ hybridization and immunohistochemistry on the same tissue section taken from anemic rat renal cortex. Left: Demonstration of Epo mRNA. Right: Double‐labeling on the same tissue section with antibody to 5‐ectonucleotidase. Cells positively stained with either technique are indicated by arrowheads. Only a minor proportion of 5′‐ectonucleotidase‐positive interstitial cells reveal Epo mRNA expression. Double‐labeled cells typically lie in angles between adjacent tubules, or between vessels and tubules. (Magnification × 800.)

(Courtesy of S. Bachmann, Berlin.) Lower panel: Topography of the production of Epo in the rat kidney. Left: The cortical labyrinth is well visualized using an enzyme histochemical technique for 5″‐nucleotidase, with the strong reaction seen as black deposits in the proximal convoluted tubule and in the fibroblasts. Right: In situ hybridization of Epo‐mRNA in the kidney of an anemic rat. The comparison of the two micrographs shows that hybridization took place in the cortical labyrinth (delimited with a dotted line), but not in the medullary rays or in the outer medulla. (Magnification: A ∼ ×62, B ∼ ×95.) [Reproduced, with permission, from ref. 265.]


Figure 8.

Temporal pattern of plasma EPO concentrations during acute hypoxia. Time‐dependent change in serum immunoreactive erythropoietin (Epo) in rats exposed to an inspiratory oxygen tension of 60 mmHg in a normobaric atmosphere. Total gas pressure was kept constant by balance nitrogen. Plasma Epo levels start to increase after a delay phase (1), then increase linearly (phase 2) to reach peak values (phase 3). Then Epo levels decline (phase 4) to reach a stable steady‐state level (phase 5).



Figure 9.

Oxygen dependency of EPO plasma peak concentrations. Peak concentrations of plasma Epo concentration in rats exposed to different inspiratory oxygen tensions for two days.



Figure 10.

Oxygen dependency of the number of erythropoietin (Epo)‐expressing cells in rat kidney cortex. Relationship between the number of Epo producing cells per square centimeter of renal cortex and the inspiratory oxygen tension in rats.



Figure 11.

Oxygen dependency of erythropoietin mRNA in primary cultured rat hepatocytes. Freshly isolated rat hepatocytes were plated on gas permeable culture supports and were exposed to different oxygen concentration in a normobaric atmosphere for 3 h.



Figure 12.

Oxygen sensing and Epo gene regulation. HIFα protein stability and transcriptional activity are regulated by PHD prolyl and FIH asparagine hydroxylases, respectively. This reaction needs oxygen, vitamin C, Fe(II) and 2‐oxoglutarate and is inhibited by succinate, fumarate, and reactive oxygen species (ROS). Upon stabilization, HIF‐2α translocates to the nucleus, heterodimerizes with HIFβ and transactivates the Epo gene.



Figure 13.

Chemical reaction scheme of HIFα prolyl‐4‐hydroxylase domain (PHD) enzymes. Prolyl residues of HIFα are hydroxylated by PHDs at the fourth carbon atom in an oxidative decarboxylation reaction that needs oxygen and 2‐oxoglutarate as co‐substrates, and ascorbate and Fe(II) as co‐factors. Succinate and CO2 are produced as co‐products. The reaction is inhibited by hypoxia, iron chelation, transition metals such as cobalt, nickel and manganese, as well as by an excess of 2‐oxoglutarate analogues such as 2‐oxalylglycine or its cell‐permeable ester dimethyloxalylglycine (DMOG).



Figure 14.

Renal oxygen sensing controlling the production of Epo.

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Article Title: Erythropoietin
 

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Roland H. Wenger, Armin Kurtz. Erythropoietin. Compr Physiol 2011, 1: 1759-1794. doi: 10.1002/cphy.c100075