Pdf regulation of erythropoietin production in a human. The human hepatoma cell line hep3b regulates its production of epo in a physiologic manner. Regulation of erythropoietin production jelkmann 2011. Loss of function of the erythropoietin receptor or jak2 in mice cells causes failure in erythropoiesis, so production of red blood cells in embryos and growth is disrupted. When anemia or hypoxia occurs, transcriptional factor, hypoxiainducible factor hif, binds to epo 5. Either hypoxia or cobalt chloride markedly increases expression of epo mrna as well as production of biologically active and. When a person who has lived at high altitude moves to a sea level environment, production of erythropoietin is suppressed, the rate of red cell production declines, and the red cell count falls until the normal sea level value is achieved. Request pdf regulation of erythropoietin production the glycoprotein hormone erythropoietin epo is an essential growth and survival factor for erythroid progenitor cells, and the rate of red. A truncated erythropoietin receptor that fails to prevent programmed cell death of erythroid cells. Renal erythropoietinproducing cells in health and disease frontiers. The expression is indicated of the different surface markers commonly used to characterise the different.
The requirement for erythropoietin starts at mature bfue and stops after the proerythroblasts stage. Epo is a survival, proliferation and differention factor for the erythrocytic progenitors, particularly the colony. Regulation of erythropoietin production request pdf researchgate. Regulation of erythropoietin production regulation of erythropoietin production eckardt, ku kurtz, a. Regulation of muscle and metabolic physiology by hypothalamic. Regulation of the erythropoietin gene blanchard 1993.
Epo production in reps is tightly regulated in a hypoxiainducible manner to maintain tissue oxygen homeostasis. This would support evidence that the bbb is relatively impermeable to epo, and brain epo has its own production and regulation that is independent of peripheral epo. Three years later, jacobson et al 2 reported that nephrectomy prevented the appearance of this factor erythropoietin in the plasma of anemic rats, and hypothesized that erythropoietin epo is produced in the kidneys. In humans and other mammals, decreased oxygen tension triggers specific and tightly regulated cellular, vascular, and erythropoietic responses. Because iron is primarily used in red blood cells, defective erythropoiesis caused by loss of the erythroid growth factor erythropoietin epo elevates iron storage levels in serum and tissues. The hormone erythropoietin epo is essential for red blood cell rbc production. Regulation of erythropoietin production fisher major. Erythropoietin, hormone produced largely in the kidneys that influences the rate of production of red blood cells erythrocytes. Adrenaline, noradrenaline and some prostaglandins 3. Epo production is controlled at the transcriptional level. The glycoprotein hormone erythropoietin epo is an essential growth and survival factor for erythroid progenitor cells, and the rate of red blood cell production is normally determined by the serum epo concentration.
Regulation of erythropoietin production, the journal of. Effects of erythropoietin on cycling performance of welltrained cyclists. Of interest in relation to the regulation of erythropoietin production is the distribution of erythropoietinproducing cells within the. Erythropoietin abbreviated as epo or epoietin, produced primarily by the kidneys, is the principal factor responsible for the regulation of red blood cell production. Whereas the sensitivity of this oxygen sensor to variations in renal oxygen supply is well. In addition to erythropoiesis, erythropoietin epo can bind the tissueprotective receptor tpr, namely eporcd1 heterodimer and plays an important role in tissue protection and immune regulation. This factor acts ona serum substrate to generate an active humoral factor, the erythropoietic stimulating factor esf or. As a response to hypoxia, a factor called erythrogenin is produced in the kidney. Hypoxic regulation of erythropoiesis and iron metabolism. Molecular biology of erythropoietin kidney international. In vivo studies in healthy human volunteers and animal models indicated that angiotensin ii ang ii and angiotensin converting enzyme inhibitors. Subsequent to that, however, it took nearly half a century before the existence of such a factor, named erythropoietin, was proven conclusively.
In 1989 recombinant human epo was approved for treatment of humans by the u. Adenosine adenosine antagonist decrease epo secretion 4. A hormone with multiple functions karger publishers. Regulation of extrarenal erythropoietin production springerlink. Regulation of erythropoietin production is related to proximal tubular function kaiuwe eckardt, armin kurtz, and christian bauer department of physiology, university ziirich, ch8057 ziirich, switzerland. The hormone erythropoietin epo maintains red blood cell mass by promoting the survival, proliferation and differentiation of erythrocytic progenitors. This feedback regulation may explain the declining epo production.
Erythropoietin production is regulated by the difference between oxygen supply and demand within the oxygen sensitive cells in the kidney. The tissuespecific regulation rationalizes the specific functions of epo produced by individual tissues, adult erythropoiesis. Kidney regulation of erythropoietin production springerlink. Chapter 1 history and biology of erythropoietin in. Mar 15, 2011 the hormone erythropoietin epo maintains red blood cell mass by promoting the survival, proliferation and differentiation of erythrocytic progenitors. Regulation of renal erythropoietin epo production is based on an intrarenal oxygen sensor. It is also important to note that epo concentration in the csf is an order of magnitude less than plasma epo concentration but still decreases with aging or hfd feeding, further. Circulating epo originates mainly from fibroblasts in the renal cortex. Erythropoietin epo produced by the kidney regulates erythropoiesis. The effect of graded haemorrhage on erythropoietin production in the immature ovine fetus. The hormone erythropoietin epo maintains red blood cell mass by promoting the. When the number of circulating red cells decreases or when the oxygen transported by the blood diminishes, an unidentified sensor detects the change, and the production. In a patient with congenital erythopoietindependent pure erythrocytosis edpe associated with hypersensitivity of erythroid progenitor cells to erythropoietin epo, the investigations planned to elucidate the mechanism responsible for hormone.
Iron is an essential mineral for oxygen delivery and for a variety of enzymatic activities, but excessive iron results in oxidative cytotoxicity. Regulation of erythropoietin production request pdf. Regulation of erythropoietin production is related to. Regulation of erythropoietin production, european journal. The relationship between the o 2 content of the blood and erythropoiesis was first described by the french anatomist francoisgilbert viault in 1890 viault, 1890, who observed a rise in rbc numbers on a journey to the highlands of peru morococha, about 4500 m. Sep 14, 2017 erythropoiesis erythropoietin regulation hematopoiesis duration.
The production of recombinant human erythropoietin. Epo production was carefully carried out under the guidelines of good industrial largescale practice gilsp, for drug production using recombinant dna technology. Hypoxia the main stimulus increased levels of hypoxia inducible factor1 hif bind to hypoxia response element on erythropoietin gene. Efficient and regulated erythropoietin production by naked. Erythropoiesis from greek erythro meaning red and poiesis meaning to make is the process which produces red blood cells erythrocytes, which is the development from erythropoietic stem cell to mature red blood cell it is stimulated by decreased o 2 in circulation, which is detected by the kidneys, which then secrete the hormone erythropoietin. Either hypoxia or cobalt chloride markedly increases expression of epo mrna as well as production of biologically active and immunologically distinct epo protein. Erythropoiesis erythropoietin regulation hematopoiesis duration.
Importantly,despitethe clinical importance of epo for patient treatment, the mechanisms for basal regulation of epo expression in the kidney is not well understood. Regulation of erythropoietin production eckardt 2005. The principal factor in the regulation of erythropoiesis is a glycoprotein hormone named erythropoietin epo. Until recently, the major site of erythropoietin epo production in the fetus was thought to be the liver, but studies have shown now that the epo gene is expressed strongly in the fetal kidney, even in the temporary mesonephros. Recent evidence suggests that epo in the cerebrum prevents neuron death and epo in the uterus induces estrogen e 2dependent uterine. You would be correct, but low o2 levels do not stimulate erythropoiesis by acting directly on the bone marrow. We have utilized the human hepatoma cell line, hep3b, to investigate the regulation of the epo gene. Dec 01, 2005 regulation of erythropoietin production regulation of erythropoietin production eckardt, ku kurtz, a. In mammals, definitive erythropoiesis first occurs in the fetal liver with progenitor cells from the yolk sac.
While it is quite likely that erythropoietin production is also regulated by hypoxia responsive mechanisms other than hif1, this strongly suggests that the hif1. Erythropoietin erythropoietin is a hormone that controls erythrocytes production, promoting survival, differentiation and proliferation of erythroid progenitor cells in the bone marrow. Efforts to understand the molecular basis of oxygenregulated erythropoiesis have led to the identi. Request pdf regulation of erythropoietin production the hormone erythropoietin epo maintains red blood cell mass by promoting the. In the first step of epo production in culture medium, frozen master clean room ground plan 9. Erythropoietin epo is the primary regulator of red blood cell development.
Epo, also known as erythropoetin, haematopoietin, or haemopoietin, is a glycoprotein cytokine secreted mainly by the kidney in response to cellular hypoxia. Regulation of erythropoietin production regulation of erythropoietin production jelkmann, wolfgang 20110315 00. Hattangadi, piu wong, lingbo zhang, johan flygare, harvey f. While it is quite likely that erythropoietin production is also regulated by hypoxiaresponsive mechanisms other than hif1, this strongly suggests that the hif1. Sites of erythropoietin production kidney international. Mechanism of erythropoietin regulation by angiotensin ii. Although hypoxic regulation of epo has been extensively studied, the mechanisms for basal regulation of epo are not well understood.
Multiple physiological functions and regulation of. Regulation of erythropoiesis by hypoxiainducible factors. Here, we investigated the effects of iron in a mouse. Hypoxia attenuates the inhibition of the epo promoter by gata2. Effects of androgen stimulation on erythropoietin production in the kidneys, and the use of the hormone estrogen in the female bone marrow 9.
We present evidence that the oxygen sensor in hep3b cells is a heme protein. The erythropoietin mechanism operates like a thermostat, increasing or decreasing the rate of red cell production in accordance with need. Diagram of the feedback regulation of erythropoiesis lack of o 2 hypoxia is a stimulus for the synthesis of erythropoietin epo, primarily in the kidneys. Oxygen sensing, hypoxiainducible factor1 and the regulation of mammalian gene expression. The concept that red blood cell production was regulated hormonally was first proposed in 1906 by carnot and deflandre. The expression is indicated of the different surface markers commonly used to characterise the different erythroidprecursors. While po2 is critical for the regulation of renal epo synthesis, some. An association between polycythemia and people living at high altitudes was first reported in 1863. Regulation of erythropoietin production is related to proximal tubular function. We show that an electric treatment in the form of highfrequency, lowvoltage electric pulses can increase more than 100fold the production and secretion of a recombinant protein from mouse skeletal muscle. Hypoxia is the fundamental stimulus for erythropoietin ep production f isher 1983, 1988. It appears that this links erythropoietin driven eyrthropoiesis with the iron mobilization needed for hemoglobin synthesis.
Role of estrogen in the regulation of erythropoietin. Our model for kidney ep production postulates that an oxygen deficit initiates a cascade of events which lead to increased biosynthesis and secretion of ep. Tissuespecific regulation of erythropoietin production in. However, it is plausible that their resident location between the capillaries and. Regulation of the erythropoietin gene blood american. The results of numerous studies, subsequently performed to test this hypothesis, provided substantial support for the concept. If you would like to request a video or topic to be made, leave a comment in the comment section below and i will try to cover it. Thinking logically you might suspect that because the primary function of erythrocytes is to transport o2 in the blood, the primary stimulus for erythrocyte production is low o2 levels. In fact, epo synthesized by these cells tends to act more locally, modulating, for example, regional angiogenesis and cell viability10. Erythropoietin epo, the hormone that stimulates red blood cell production, is synthesized in the kidney and liver in response to hypoxia.
Regulation of erythropoietin production in a human hepatoblastoma cell. The glycoprotein hormone erythropoietin epo is an essential growth and survival factor for erythroid progenitor cells, and the rate of red blood cell production is normally determined by the. Physiology and pathophysiology of renal erythropoietinproducing. Mar 15, 2011 regulation of erythropoietin production regulation of erythropoietin production jelkmann, wolfgang 20110315 00. New insights into molecular mechanisms of oxygen homeostasis hematologyoncology clinics of north america, vol. Mar 14, 2011 the hormone erythropoietin epo maintains red blood cell mass by promoting the survival, proliferation and differentiation of erythrocytic progenitors. Regulation of erythropoietin production and recent trends in anaemia therapy but may contribute to induce stress erythropoiesis9. That erythropoietin production and regulation of the oxygen carrying capacity of the blood should be the response of the renal fibroblasts might be regarded as surprising. Therapeutical erythopoietin epo levels were achieved in mice with a single injection of as little as 1.
The hypoxic stimulation of epo production is largely due to the transcriptional activation of the epo gene, although the prolongation of mrna halflife may also play a partial role. Hypoxia attenuates the inhibition of the epo promoter by gata. Erythropoietin epo, the hormone that stimulates red blood cell production, is induced by hypoxia. Regulation of erythropoietin production jelkmann 2011 the. Regulation of erythropoietin production, european journal of. Developmental regulation of erythropoietin and erythropoiesis. Regulation of extrarenal erythropoietin production.