Erythropoietin regulation

Anemia may be present in some patients due to impaired erythropoietin regulation, nutritional factors (vitamin E and iron malabsorption), or chronic inflammation. With chronic pulmonary disease, increased cytokine production can lead to shortened red blood cell survival, reduced erythropoietin response, and impaired mobilization of iron stores. 

Bahlmann FH, De Groot K, Spandau JM, Landry AL, Hertel B, Duckert T, Boehm SM, Menne J, Haller H, Fliser D. Erythropoietin regulates endothelial progenitor cells. Stood 2004 103 921-926. 

Anemia is observed in some CF patients despite chronic hypoxia. The apparent deficient erythroid response occurs, at least in part, from disturbances in erythropoietin regulation and iron availabihty (impaired gastrointestinal absorption). Despite chronic hypoxia in some patients with CF, erythropoietin concentrations are normal or low. The condition is characterized by decreased hematocrit and serum ferritin, increased carboxyhemoglobin, and normal or low hemoglobin. Vitamin E concentrations may be normal. Many patients may have iron deficiency owing to decreased dietary intake, malabsorption, or blood loss. 

Center for Biologies Evaluation and Research (CBER). This center is responsible for the regulation and approval of ah biological products intended for use in the treatment, prevention, or cure of diseases or injuries to humans. A biological product is any vims, therapeutic semm, toxin, antitoxin, vaccine, blood or blood component or derivative, or analogous product (5). It also includes products produced by biotechnology, such as interferons and erythropoietins. 

There are undifferentiated stem cells of the blood elements in the bone marrow that differentiate and mature into erythrocytes, (red blood cells), thrombocytes (platelets), and white blood cells (leukocytes and lymphocytes). The production of erythrocytes is regulated by a hormone, erythropoietin (see the section on kidney toxicity), that is synthetized and excreted by the kidney. An increase in the number of premature erythrocytes is an indication of stimulation of erythropoiesis, i.e., increased production of erythrocytes in anemia due to continuous bleeding. 

Erythropoietin (Eprex ) is physiologically produced in the kidney and regulates proliferation of committed progenitors of red blood cells. It is used to substitute erythropoietin in severe anemias due to end stage renal disease or treatment of cancer with cytostatic agents. Side effects include hypertension and increased risk of thrombosis. 

Anemia may occur in patients with chronic renal failure as tlie result of the inability of the kidney to produce erythropoietin. Erythropoietin is a glycoprotein hormone synthesized mainly in the kidneys and used to stimulate and regulate the production of erythrocytes or red blood cells (RBCs). Failure to produce the needed erythrocytes results in anemia Two examples of drug used to treat anemia associated with chronic renal failure are epoetin alfa (Epogen) and darbepoetin alfa (Aranesp). 

Human erythropoietin is a glycoprotein of 166 amino acids (molecular mass about 34 kDa). Its amount in plasma can be measured by radioimmunoassay. It is the major regulator of human erythropoiesis. Erythropoietin is synthesized mainly by the kidney and is released in response to hypoxia into the bloodstream, in which it travels to the bone marrow. There it interacts with progenitors of red blood cells via a specific receptor. The receptor is a transmembrane protein consisting of two different subunits and a number of domains. It is not a tyrosine kinase, but it stimulates the activities of specific... 

Erythropoietin is a glycoprotein hormone that regulates the proliferation, differentiation, and maturation of erythroid cells. The EPO receptor is a member of the class 1 cytokine receptor superfamily. The crystal structure of an EPO-mimetic peptide and the extracellular portion of the... 

Although the kidneys are not considered endocrine glands per se, they are involved in hormone production. Erythropoietin is a peptide hormone that stimulates red blood cell production in bone marrow. Its primary source is the kidneys. Erythropoietin is secreted in response to renal hypoxia. Chronic renal disease may impair the secretion of erythropoietin, leading to development of anemia. The kidneys also produce enzymes. The enzyme renin is part of the renin-angiotensin-aldosterone system. As will be discussed, these substances play an important role in the regulation of plasma volume and therefore blood pressure. Other renal enzymes are needed for the conversion of vitamin D into its active form, 1,25-d i hyd ro xyv itamin D3, which is involved with calcium balance. 

Biomedical research continues to broaden our understanding of the molecular mechanisms underlining both health and disease. Research undertaken since the 1950s has pinpointed a host of proteins produced naturally in the body that have obvious therapeutic applications. Examples include the interferons and interleukins (which regulate the immune response), growth factors, such as erythropoietin (EPO which stimulates red blood cell production), and neurotrophic factors (which regulate the development and maintenance of neural tissue). 

The other hormone of note synthesized by kidney is erythropoietin (EPO), a glycosylated peptide hormone (molecular weight approximately 50 000), which promotes red blood cell formation and is secreted in response to poor oxygen perfusion (hypoxia) of the kidney. This, along with the control of blood pressure via the RAA system illustrates the importance of the kidney in regulating aspects of the blood vascular system. Further details of EPO can be found in Chapter 5. 

Erythropoietin is a peptide hormone that is formed predominantly by the kidneys, but also by the liver. Together with other factors known as colony-stimulating factors" (CSF see p.392), it regulates the differentiation of stem cells in the bone marrow. 

Many cytokines play a regulatory role in processes other that immunity and inflammation. Neurotrophic factors such as nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF) regulate growth, development and maintenance of various neural populations in the central and peripheral nervous system. Erythropoietin stimulates the production of red blood cells from erythroid precursors in the bone marrow. 

Erythropoietin (EPO) is an additional haemopoietic growth factor. It is primarily responsible for stimulating and regulating erythropoiesis (i.e. erythrogenesis, the production of red blood cells) in mammals. 

Physiologically, oxygen transport to metabolising tissues is provided by haemoglobin contained within erythrocytes. This pathway starts in the bone marrow with immunohaematopoietic stem cells that differentiate to progenitors which proliferate to yield the recognisable normoblasts. The latter mature to reticulocytes, which are then released into the circulation. Overall regulation is primarily mediated by the renal hormone called erythropoietin. 

Abruzzese, R.V., D. Godin, V. Mehta, J.L. Perrard, M. French, W. Nelson, G. Howell, M. Coleman, B.W. O Malley, and J.L. Nordstrom, Ligand-dependent regulation of vascular endothelial growth factor and erythropoietin expression by a plasmid-based autoinducible GeneSwitch system. Mol Ther, 2000. 2(3) 276-87. 

Erythropoietin stimulates erythroid proliferation and differentiation by interacting with erythropoietin receptors on red cell progenitors. The erythropoietin receptor is a member of the JAK/STAT superfamily of cytokine receptors that use protein phosphorylation and transcription factor activation to regulate cellular function (see Chapter 2). Erythropoietin also induces release of reticulocytes from the bone marrow. Endogenous erythropoietin is primarily produced in the kidney. In response to tissue hypoxia, more erythropoietin is produced through an increased rate of transcription of the... 

A variation on the basic theme of receptor Tyr kinases is seen in receptors that have no intrinsic protein kinase activity but, when occupied by their ligand, bind a soluble Tyr kinase. One example is the system that regulates the formation of erythrocytes in mammals. The cytokine (developmental signal) for this system is erythropoietin (EPO), a 165 amino acid protein produced in the kidneys. When EPO binds to its plasma membrane receptor (Fig. 12-9), the receptor dimerizes and can now bind the soluble protein kinase JAK (Janus kinase). This binding activates JAK, which phosphory-lates several Tyr residues in the cytoplasmic domain of the EPO receptor. A family of transcription factors, collectively called STATs (signal transducers and activators of transcription), are also targets of the JAK kinase activity. An SH2 domain in STATS binds (P)-Tyr residues in the EPO receptor, positioning it for this phosphorylation by JAK. When STATS is phosphorylated in re-... 

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