Improvement of anemia in W/WV mice by recombinant human erythropoietin (rHuEPO) mediated through EPO receptors with lowered affinity.
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.
Kabaya
K
K
Pharmaceutical Research Laboratory, Kirin Brewery Co., Ltd., Gunma, Japan.
Akiyama
H
H
Nishi
N
N
Misaizu
T
T
Okada
Y
Y
Kawagishi
M
M
Amano
K
K
Kusaka
M
M
Seki
M
M
Uzumaki
H
H
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
D006454:Hemoglobins; D017467:Receptors, Erythropoietin; D011994:Recombinant Proteins; D004921:Erythropoietin