Erythropoietin is the hematopoietic hormone secreted by the kidney that functions as a major stimulator for the production of erythrocytes. Erythropoietin is a secreted glycoprotein of 165 amino acids, but with a mature molecular mass of 30–34 kDa due to the presence of a significant amount of covalently linked carbohydrate. Hypoxia (a low-oxygen environment) can stimulate the synthesis of erythropoietin mRNA in the renal capillary tubular cells by unknown mechanism(s). In the adult human, erythropoietin is a classic hormone, secreted by the kidney and transported systemically to its site of action in the erythron.

Each molecule of hemoglobin is composed of two paired amino acid chains of α2β2 with a molecular weight of ~16,000. The four heme prosthetic group is synthesized in the cytosol and mitchondria of the immature red blood cells; see the proerythroblasts, basophillic erythroblasts, and erythroblasts in Figure 1, panel C. Each heme group binds one O2 and the intact hemoglobin molecule α2β2 normally carries four oxygen O2 molecules linked to four separate heme groups. The intact human erythrocytes survive only ~120 days, which justifies the necessity for a vigorous production of erythrocytes in the bone marrow.

Fig1. Role of the kidney in blood erythropoiesis. (A) Illustration of the collaboration between the kidney as a source of the hormone erythropoietin and the skeletal system as a bone marrow site to biosynthesize hemoglobin for the red blood cells. The protein hormone erythropoietin (EPO) is critical for the production of the red blood cells for the whole body. The renal cortex of the kidney is the source of production of EPO. When the kidney senses the lack of oxygen (hypoxia is the condition when oxygen is lower than the normal level) it mobilizes the production and secretion of the glycoprotein hormone, erythopoietin (EPO). EPO is biosynthesized in the peritubular capillary lining cells of the renal cortex region of the kidney (see Figure 15-1A). The EPO then moves through the circulatory system and ultimately binds to the EPO receptors associated with proerythroblasts present in the bone marrow of the entire skeleton. This is the site of production of the hemoglobin that is produced for all the red blood cells. (B) Mode of action of erythropoietin in the regulation of gene expression. After the secretion of erythropoietin into the circulatory system, it ultimately is taken up by erythrocytic progenitor myeloid stem cells present in the bone marrow. One erythropoietin hormone molecule binds to two collaborative receptors present in the cell membrane of myeloid stem cells. The receptors activate the JAK2 and STATS pathways of PI3K – Akt/PKB, Ras-MAPK, and the NF-kB pathway. Collectively these pathways stimulate the production of differentiation and growth of the myeloid stem cells into intermediate cell types (basophillic erythroblasts and then more mature erythroblasts that have lost their nucleus). (C) Summary of the process of erythropoiesis which throughout life is producing new erythrocytes necessary to transport oxygen to all cells in the body. The starting point is activation of the myeloid stem cell, followed by differentiation into proerythroblasts, basophillic erythroblasts, with their cell nucleus and then without their cell nucleus, followed by differentiation into the final reticulocyte, which can join the large family of erythrocytes.

The important biological property of EPO is that it is anti-apoptotic. See Figure 1B. Thus, when EPO binds to the erythopoietin receptor as a homodimer in the plasma membrane, it results in the activation of the cytoplasmic Janus-2 kinases (JAK2) pathway which catalyzes the phosphorylation of tyrosine residues of the EPO-receptor as well as of intracellular proteins (transcription factors and enzymes). Collectively these actions facilitate the production and maturation of the reticulocytes in the bone marrow compartment which supports the essential differentiation and growth properties of the myeloid stem cells.

Figure 1C illustrates a summary of the process of erythropoiesis which throughout life is producing new erythrocytes necessary to transport oxygen to all cells in the body. This is dependent upon converting the myeloid stem cell successfully into proerythroblasts, then basophillic erythroblasts, erythroblasts (with and then without a nucleus), and finally into reticulocytes. They are then released/secreted and circulate in the body’s blood compartment for ~1 day while they complete development into mature erthrocyte red blood cells.

The red blood cells are functionally active for ~3–4 months and then they begin to deteriorate. This is because the red blood cell’s membranes have become fragile as a result of many passages through narrow arterioles and capillaries, which can physically disrupt and break the red blood cell. These damaged red blood cells are eventually taken out of the general circulation when they pass through the spleen, which breaks them down further. Also the iron is released from the hemoglobin group and is recycled to be incorporated into a new red blood cell.

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مواضيع ذات صلة

Hemoglobin

Adrenomedullin

Kallikreins and Kinins

Biological Actions of NO

Biological Actions of Endothelins

Red Blood Cell Enzymopathies- Metabolic Pathways

Hemoglobins with Decreased Oxygen Affinity

Chemistry, Biosynthesis, and Secretion of Nitric Oxide System

Chemistry, Biosynthesis, and Secretion of Endothelins

Chemistry, Biosynthesis, and Secretion of ANP

Hemoglobins with Increased Oxygen Affinity

Specific Enzymes are Associated with Compartments Separated by the Mitochondrial Membranes