PHYSIOLOGICAL REVIEWS Vol. 72, No. 2, April 1992 Printed in U.S.A. Erythropoietin: Structure, Control of Production, and Function WOLFGANG JELKMANN Physiologisches Institut I, Universit&! Bonn, Bonn, Federal Republic of Germany I. Introduction ......................................................................................... 449 II. Historical Background .............................................................................. 450 III. Biochemical Aspects ................................................................................. 451 A. Molecular biology ................................................................................ 451 B. Structure of erythropoietin ...................................................................... 452 C. Assay methods, standardization, and normal plasma values ................................... 453 IV. Sites of Production .................................................................................. 454 A. Kidney ............................................................................................ 454 B. Extrarenal sites .................................................................................. 455 V. Tissue Hypoxia as Stimulus of Erythropoietin Production ......................................... 456 A. Whole organism .................................................................................. 456 B. Isolated organs and cell cultures ................................................................ 458 VI. Paracrine and Endocrine Modulators of Erythropoietin Production ............................... 461 A. Local messengers ................................................................................ 461 B. Hypothalamus and humoral messengers ........................................................ 461 VII. Kinetics of Erythropoietin in Plasma ............................................................... 463 A. Dynamic of formation ........................................................................... 463 B. Metabolism ....................................................................................... 463 VIII. Mechanism of Action of Erythropoietin ............................................................ 464 A. Erythropoietin-responsive cells ................................................................. 464 B. Erythropoietin receptor ......................................................................... 465 C. Signal transduction .............................................................................. 466 IX. Pathophysiology of Production of Erythropoietin .................................................. 467 A. Overproduction ................................................................................... 467 B. Deficiency ........................................................................................ 468 X. Clinical Application ................................................................................. 469 A. Replacement therapy in renal failure ........................................................... 469 B. Pharmacological use in other anemias .......................................................... 470 XI. Comments ........................................................................................... 471 I. INTRODUCTION Hemopoiesis counterbalances the continuous loss of aged blood cells. Young progeny are generated by my- eloid and lymphoid progenitors that originate from a small pool of pluripotent stem cells. Blood cell counts are fairly constant in health. The rates of the prolifera- tion and differentiation of blood cell lineage-specific progenitors can greatly increase in response to dis- orders such as hemorrhage or infection. Hemopoiesis is controlled by several glycoprotein hormones and paracrine peptides. Apart from erythro- poietin, these include thrombopoietin (415), at least three different myeloid colony-stimulating factors (GM-CSF, G-CSF, M-CSF) in the granulocytic-mono- cytic lineage (122, 431, 522), and the various interleu- kins, which not only activate the lymphocytic system but also modulate the rate of proliferation of myeloid progenitors (21, 431, 489, 522). Several of the human genes coding for hemopoietic growth factors have been isolated and cloned recently. The recombinant proteins are available for studies of their structure and function and for therapeutic purposes. Erythropoietin is an essential growth factor in the erythrocytic lineage. One percent of all red blood cells are destroyed daily and replaced by reticulocytes in healthy humans. The basal production rate of 2-3 X 1011 cells/day greatly increases when the blood O2 availabil- ity is lowered. Lack of O2 induces erythropoietin gene expression in the kidneys (38,52,586) and the liver (38, 52). The plasma level of erythropoietin may rise l,OOO- fold above normal in severe anemia or hypoxemia. Purification of a few milligrams of the hormone from human urine was accomplished by Miyake et al. (453) in 1977. This work was a landmark in erythropoie- tin research. The pure urinary protein enabled investi- gators to carry out the first reliable radioimmunoassays for the hormone (95, 228, 597) instead of the laborious 0031-9333/92 $2.00 Copyright 0 1992 the American Physiological Society 449