Preface

The involvement of a humoral factor (named as haemopoietin) in the regulation of hematopoiesis, was firstly described in literature in 1906. However, only 40 years later a linkage between erythropoietin (EPO) and erythropoiesis was described, and only in the 1950s was established that the kidney is the main site of production of EPO. The nucleotide sequence of human EPO gene was determined in 1985 and the cloning and expression of the gene led to the production of recombinant human EPO (rhEPO). The first clinical trial using rhEPO in the treatment of the anemia of end-stage renal disease was published in 1987, and, nowadays, rhEPO is currently used for the treatment of anemia of these patients, as well as for a variety of other clinical situations associated with anemia, namely prematurity, HIV infection and non-myeloid malignancy; as supportive therapy in post chemotherapy, post transplantation and as an alternative to blood transfusion in some clinical situations.

In the last years, the research in this area increased significantly focusing different interesting issues, namely, how to increase half-life of EPO, to found different routes of administration and new erythropoietic-stimulating agents (ESA) or modified EPO molecules. Moreover, in literature there is increased evidence that EPO present other effects beyond erythropoietic-stimulation. These pleiotropic effects of EPO appear to result from the existence of two different EPO receptors (EPOR) with different affinities for EPO. In erythroid cells, EPO bind to the EPOR homodimers, whereas on the other cells and tissues, higher local EPO concentrations are needed to trigger the activation of a heterodimer EPOR, which is expressed in different tissues, namely brain, heart and kidney.

The discovery of new EPO actions beyond the hematopoietic system opened a new field of investigation with these agents. Several molecules have been developed to present the protective action, without the activation of the hematopoietic system. These agents can be potentially used in several diseases of the brain/central and peripheral nervous system, eye, heart and kidney.

This volume of “Frontiers in Drug Discovery” starts with the revision of erythropoiesis (chapter 1), EPO gene regulation (chapter 2), microRNAs and potential contribution to the development of new therapeutic strategies (chapter 3), animal models for studding kidney disease-associated anemia (chapter 4) and risk and benefits of ESA therapy (chapter 5 and 6). In chapter 7 and 8, the biological effects of the new erythropoietic stimulating agents, heparin-binding erythropoietin and of pHBSP, were presented. The remaining chapters of this book show some of the potential applications of erythropoietic stimulating agents.