title: Improvement of anemia in W/WV mice by recombinant human erythropoietin (rHuEPO) mediated through EPO receptors with lowered affinity.
abstract: We studied the effects of recombinant human erythropoietin (rHuEPO) on anemic W/WV mice which manifested severe anemia accompanied by mutation of the W gene encoding tyrosine kinase type receptor (c-kit gene) of bone marrow hematopoietic cells. Nine-week-old male W/WV mice or normal littermates (+/+) were used. Since serum EPO concentration in W/WV mice increased in proportion to severity of anemia, EPO production in the kidneys of these animals was found to be regulated normally. Hematocrit in +/+ mice increased and a maximal response was also obtained with 2,000 IU/kg of rHuEPO. On the other hand, hematocrit in W/WV mice increased in a dose-responsive manner by administration with 2,000 and 10,000 IU/kg, showing different responses to rHuEPO in these two types of mice. The responsiveness of W/WV mice to rHuEPO was low in terms of increases in erythroblastic precursor cells (CFU-E), and immature cells in the bone marrow. Scatchard analysis of the specific binding of 125I-rHuEPO against bone marrow cells revealed that the different responsiveness to rHuEPO between W/WV and +/+ mice may be correlated with differences in affinity of EPO receptor of bone marrow cells in these mice. From these results, a high dose of rHuEPO is capable of improving the anemia in W/WV mice that had EPO receptors with lowered affinity, indicating the possible effectiveness of rHuEPO in anemic patients with EPO receptor abnormality.
authors.affiliation: Pharmaceutical Research Laboratory, Kirin Brewery Co., Ltd., Gunma, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Kabaya
authors.forename: H
authors.initials: H
authors.lastname: Akiyama
authors.forename: N
authors.initials: N
authors.lastname: Nishi
authors.forename: T
authors.initials: T
authors.lastname: Misaizu
authors.forename: Y
authors.initials: Y
authors.lastname: Okada
authors.forename: M
authors.initials: M
authors.lastname: Kawagishi
authors.forename: K
authors.initials: K
authors.lastname: Amano
authors.forename: M
authors.initials: M
authors.lastname: Kusaka
authors.forename: M
authors.initials: M
authors.lastname: Seki
authors.forename: H
authors.initials: H
authors.lastname: Uzumaki
mesh_terms: D000740:Anemia / Q000188:drug therapy*; D000818:Animals; D001853:Bone Marrow / Q000378:metabolism; D001854:Bone Marrow Cells; D015672:Erythroid Precursor Cells / Q000166:cytology / Q000378:metabolism; D004920:Erythropoiesis / Q000187:drug effects*; D004921:Erythropoietin / Q000378:metabolism / Q000627:therapeutic use*; D006400:Hematocrit; D006454:Hemoglobins / Q000378:metabolism; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D017467:Receptors, Erythropoietin / Q000502:physiology; D011994:Recombinant Proteins
chemical_list: D006454:Hemoglobins; D017467:Receptors, Erythropoietin; D011994:Recombinant Proteins; D004921:Erythropoietin