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Evidence of receptor-mediated elimination of erythropoietin by analysis of erythropoietin receptor mRNA expression in bone marrow and erythropoietin clearance during anemia.

ABSTRACT: Erythropoietin (Epo) is the primary hormone that stimulates erythroid proliferation and differentiation through its cell surface receptor (EpoR) on erythroid progenitor cells. Previous studies have suggested that the bone marrow plays an important role in Epo's elimination. The changes in the EpoR mRNA levels and Epo's clearance in the bone marrow of 11 newborn lambs were studied to elucidate the role of EpoR in Epo's clearance under anemic conditions. Epo mRNA levels were measured by real-time polymerase chain reaction, and relative expression of EpoR was calculated by using the comparative CT method. The glyceraldehyde-3-phosphate dehydrogenase housekeeping gene was chosen as a control gene for the calculations. All lambs showed significant increase in bone marrow EpoR mRNA levels after phlebotomy-induced anemia. Epo's clearance determined from simultaneous pharmacokinetic studies with 125I-recombinant human Epo showed a significant increase after phlebotomy-induced anemia that was similar to the increase in EpoR. By day 28 after phlebotomy, EpoR mRNA levels and Epo clearance had returned toward baseline. These results indicate that the changes in Epo's clearance are not caused by body growth but result from significant changes in the pool of EpoR. A linear mixed-effect model was used to evaluate the quantitative relationship between EpoR and Epo's clearance. This analysis demonstrated a highly significant positive linear correlation between EpoR and Epo clearance. Together, these findings provide strong evidence that receptor-mediated Epo clearance is an important route for Epo's elimination.

SUBMITTER: Nalbant D

PROVIDER: S-EPMC2872962 | biostudies-literature | 2010 May

REPOSITORIES: biostudies-literature

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Evidence of receptor-mediated elimination of erythropoietin by analysis of erythropoietin receptor mRNA expression in bone marrow and erythropoietin clearance during anemia.

Nalbant Demet D Saleh Mohammad M Goldman Frederic D FD Widness John A JA Veng-Pedersen Peter P

The Journal of pharmacology and experimental therapeutics 20100126 2

Erythropoietin (Epo) is the primary hormone that stimulates erythroid proliferation and differentiation through its cell surface receptor (EpoR) on erythroid progenitor cells. Previous studies have suggested that the bone marrow plays an important role in Epo's elimination. The changes in the EpoR mRNA levels and Epo's clearance in the bone marrow of 11 newborn lambs were studied to elucidate the role of EpoR in Epo's clearance under anemic conditions. Epo mRNA levels were measured by real-time ...[more]

PMID: 20103588

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Project description:Feeding cadmium chloride (50 or 1000 ppm CdCl2 in drinking water, ad libitum) to C57BL/6 mice resulted in a significant and sustained fall in blood erythrocyte count and hemoglobin levels that started 4 and 3 weeks after the start of 50 and 1000 ppm cadmium doses respectively. A transient yet significant reticulocytosis occurred during the first 4 weeks of cadmium treatment. Using the recently developed double in vivo biotinylation (DIB) technique, turnover of erythrocyte cohorts of different age groups was simultaneously monitored in control and cadmium treated mice. A significant accumulation of younger erythrocytes and a concomitant decline in the relative proportions of older erythrocytes in circulation was observed in both 50 and 1000 ppm cadmium groups indicating that older erythrocytes were preferentially eliminated in cadmium induced anemia. A significant increase in the erythropoietin levels in plasma was seen in mice exposed to 1000 ppm cadmium. Levels of inflammatory cytokines (IL1A, IL6, TNF?, IFN?) were however not significantly altered in cadmium treated mice. A significant increase in cellular levels of reactive oxygen species (ROS) was observed in older erythrocytes in circulation but not in younger erythrocytes. Erythropoietic activity in the bone marrows and spleens of cadmium treated mice was examined by monitoring the relative proportion of cells belonging to the erythroid line of differentiation in these organs. Erythroid cells in bone marrow declined markedly (about 30%) in mice in the 1000 ppm cadmium group but the decline was not significant in the 50 ppm cadmium group. Cells representing various stages of erythroid differentiation in bone marrow and spleen were enumerated flow cytometrically by double staining with anti-Ter119 and anti-transferrin receptor (CD71) monoclonal antibodies. Decline of erythroid cells was essentially confined to pro-erythroblast and erythroblast-A, along with a concurrent increase in the splenic erythroid population indicating a stress response. In short cadmium exposure causes preferential clearance of older erythrocytes from circulation along with a depressed erythropoietic activity at higher doses.

Dataset Information

Evidence of receptor-mediated elimination of erythropoietin by analysis of erythropoietin receptor mRNA expression in bone marrow and erythropoietin clearance during anemia.

Publications

Evidence of receptor-mediated elimination of erythropoietin by analysis of erythropoietin receptor mRNA expression in bone marrow and erythropoietin clearance during anemia.

Similar Datasets

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