%0 Journal Article %A Demet Nalbant %A Mohammad Saleh %A Frederic Goldman %A John Widness %A Peter Veng-Pedersen %T Evidence of receptor-mediated elimination of erythropoietin by analysis of Epo receptor mRNA expression in bone marrow and erythropoietin clearance during anemia. %D 2010 %R 10.1124/jpet.109.163568 %J Journal of Pharmacology and Experimental Therapeutics %P jpet.109.163568 %X Erythropoietin (Epo) is the primary hormone that stimulates the 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 morrow 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 PCR and relative expression of EpoR was calculated using the comparative CT method (ΔΔCT). The GAPDH house keeping gene was chosen as a control gene for the calculations. All lambs showed significant increase in bone marrow EpoR mRNA levels following phlebotomy-induced anemia. Epo's clearance determined from simultaneous pharmacokinetic studies with 125I-rHuEpo showed a significant increase following phlebotomy-induced anemia that was similar to the increase in EpoR. By day 28 post phlebotomy, EpoR mRNA levels and Epo clearance had returned back toward baseline. These results indicate that the changes in Epo's clearance are not due to 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.The American Society for Pharmacology and Experimental Therapeutics %U https://jpet.aspetjournals.org/content/jpet/early/2010/01/26/jpet.109.163568.full.pdf