Erythropoietin treatment for anemia and hematopoietic/erythroid progenitor cell responses

National Institute Of Diabetes And Digestive And Kidney Diseases

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Abstract

Erythropoietin is required for red blood cell production. Mice treated with high dose erythropoietin to increase hematocrit showed improvement in glucose tolerance in young and old mice and in both males and females. Male mice also exhibited erythropoietin regulation of fat mass, especially in aged mice, suggesting that erythropoietin regulation of glucose tolerance may be related to the increase in erythropoietic activity but does not require change in fat mass. In mice, age, sex and fat mass and erythropoietin receptor expression in adipose tissue modulated the change in glucose tolerance with erythropoietin treatment. The increased erythropoietic response and the increased requirement for energy associated with increased cell proliferation explain in part the decrease in glucose level and improvement in glucose tolerance with erythropoietin stimulation. However, metabolic response of other non-erythroid tissue may also contribute to improved glucose tolerance. The link between nitric oxide production and hydroxycarbamide induction of human fetal hemoglobin and nitric oxide-dependent increase in erythropoiesis in a mouse model of chronic stress provided evidence for a role for nitric oxide synthase in erythropoietin stimulated erythropoiesis. Erythropoietin promoted endothelial nitric oxide synthase (NOS3) production in endothelial cells and corresponding nitric oxide production. However, in mice that lack NOS3, hematocrit was not affected and treatment with exogenous erythropoietin resulted in increased hematocrit comparable to wild type mice. In cultures of corresponding primary bone marrow cells, erythroid colony assays were also comparable to wild type mice and high and low erythropoietin concentrations. Unlike the NOS3 knockout mice, mice that lack neuronal nitric oxide synthase (NOS1) exhibited lower hematocrit and a blunted erythropoietic response to exogenous EPO treatment. Cultures of primary bone marrow cells from NOS1 knockout mice exhibited colony formation at low erythropoietin concentration comparable to cultures from wild type mice bone marrow, but colony size and number were decreased at high erythropoietin concentration compared with cultures from wild type mice. Transplantation of bone marrow cells from NOS1 knockout mice into wild type mice also showed decreased erythropoietic response to erythropoietin stimulation compared with wild type bone marrow cell transplantation. These data indicated that NOS1 contributes importantly to erythropoietic maintenance and response to endogenous erythropoietin and to erythropoietin treatment. Assessments of erythropoiesis in mouse models of disrupted nitric oxide synthase revealed that knockout of neuronal nitric oxide synthase (NOS1) blunted erythropoietin stimulated erythropoiesis that was not observed in knockout of endothelial nitric oxide synthase (NOS3). Hydroxyarbamide stimulation of erythroid progenitor cells and fetal hemoglobin induction associated with treatment for sickle cell anemia have been suggested to be influenced by contributions from inducible nitric oxide synthase (NOS2) and nitric oxide production. Hydroxycarbamide treatment of erythroid cultures caused cells to arrest in S-phase by inhibiting ribonucleotide reductase and DNA synthesis, increased NOS2 and nitric oxide release, and increased NOS-dependent synthesis of fetal hemoglobin. Knockdown of NOS2 prevented hydroxycarbamide reduction in proliferation and induction of apoptosis, indicating that NOS2 mediates hydroxycarbamide inhibition of proliferation and stimulation of apoptosis in erythroid cells. In general, treatment in sickle cell disease by agents such as hydroxycarbamide to induce fetal hemoglobin may be directly affected by NOS2. In studies related to kidney production of erythropoietin, clear-cell renal cell carcinoma was associated with von Hippel-Lindau gene mutation thought to activate hypoxia-inducible factor 1A and hypoxia responsive genes such as erythropoietin. Analysis of clear-cell renal cell carcinoma tumor from 43 patients revealed 27 somatic mutations in the von Hippel-Lindau gene but that erythropoietin activation in renal carcinoma was mainly driven by low oxygen and not von Hippel-Lindau regulation of hypoxia-related responses. During the three decades that erythropoietin has been used to treat anemia including anemia associated with cancer treatment, it has been suggested that erythropoietin stimulation might compete with development and differentiation of non-erythroid hematopoietic cells such as neutrophils. Reanalysis of available primary data from 5 trials of erythropoietin treatment in cancer patients from the Yale Open Data Access project showed that severe neutropenia was greater among study subjects assigned to erythropoietin treatment indicating that erythropoietin treatment may be associated with myeloid-erythroid lineage competition Full knowledge of the erythropoietic and non-erythroid tissue response to endogenous and exogenous erythropoietin will be informative on the erythropoietic and metabolic effects associated with high dose erythropoietin, erythropoietin derivatives or erythropoietin-inducible drugs.