The regulation of erythropoiesis by selenium in mice.
Redox modulation by antioxidants, such as selenium (Se), has emerged as an important regulator of erythropoiesis. Using Se-deficient (0.04 ppm), Se-adequate (0.1 ppm), and Se-supplemented (0.4 ppm) C57/BL6 mice, we show that Se deficiency caused anemia, when compared to the Se-supplemented and Se-adequate groups. Increased denaturation of hemoglobin, methemoglobin, protein carbonyls, lipid peroxidation, Heinz bodies, and osmotic fragility of erythrocytes were observed in Se-deficient mice. Increased oxidative stress upregulated forkhead transcription factor (FoxO3a) and hypoxia-inducible factor-(HIF)1α in the spleen and kidney of Se-deficient murine as well as in the proerythroblast G1E cells cultured in Se-deficient media. A significant increase in the expression of erythropoietin, a downstream target of HIF1α, and expansion of stress erythroid progenitors (burst forming units-erythroid) were seen in the Se-deficient mice. Despite the increase in erythroid progenitors, lowered reticulocytes suggest a defective erythroid differentiation pathway. While Se deficiency led to increased nuclear levels of active FoxO3a, Se-adequate conditions reversed this effect and increased nuclear export by its binding partner, 14-3-3βζ, that is under the redox control of selenoproteins. In summary, these results provide insight into the importance of adequate Se nutrition in regulating red cell homeostasis by mitigating oxidative stress-dependent modulation of FoxO3a and HIF1α to effect differentiation of erythroid progenitors.
Kaushal
Naveen
N
Department of Veterinary and Biomedical Sciences, Center for Molecular Immunology and Infectious Disease, The Pennsylvania State University, University Park, PA 16802, USA.
Hegde
Shailaja
S
Lumadue
Jeanne
J
Paulson
Robert F
RF
Prabhu
K Sandeep
KS
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D002478:Cells, Cultured; D019587:Dietary Supplements; D004912:Erythrocytes / Q000187:drug effects* / Q000378:metabolism; D004920:Erythropoiesis / Q000187:drug effects*; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D012643:Selenium / Q000008:administration & dosage / Q000172:deficiency / Q000494:pharmacology*
D000975:Antioxidants; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012643:Selenium