Jiang Xingkang, Gao Ming, Chen Yue, Liu Jing, Qi Shiyong, Ma Juan, Zhang Zhihong, Xu Yong
Department of Urology, The Second Hospital of Tianjin Medical University, Tianjin Institute of Urology, Tianjin 300211, China.
State Key Laboratory of Environment Chemistry and Ecotoxicology, Research Center for Eco-Environmental Science, Chinese Academy of Sciences, Beijing 100085, China.
Blood Cells Mol Dis. 2016 May;58:45-51. doi: 10.1016/j.bcmd.2016.02.005. Epub 2016 Feb 19.
Hemolytic anemia is a common form of anemia due to hemolysis, resulting in disordered iron homeostasis. In this study, a dose of 40mg/kg phenylhydrazine (PHZ) was injected into mice to successfully establish a pronounced anemia animal model, which resulted in stress erythropoiesis and iron absorption. We found that serum erythropoietin (EPO) concentration was dramatically elevated by nearly 5000-fold for the first 2days, and then drop to the basal level on day 6 after PHZ injection. Mirrored with serum EPO concentration, the mRNA expression of erythroferrone (ERFE) was rapidly increased in the bone marrow and spleen 3days after injection of PHZ, and then gradually decreased but was still higher than baseline on day 6. In addition, we also found that the hepcidin mRNA levels were gradually reduced almost up to 8-fold on day 5, and then was ameliorated compared to the untreated control. Mechanistic investigation manifested that the increase of serum EPO essentially determined the induction of ERFE expression particular at the first 3days after PHZ treatment. Lentiviral mediated ERFE knockdown significantly restrained hepcidin suppression under PHZ treatment. Thus, our data unearthed EPO-dependent ERFE expression acts as an erythropoiesis-driven regulator of iron metabolism under PHZ-induced hemolytic anemia.
溶血性贫血是由于溶血导致的一种常见贫血形式，会引起铁稳态紊乱。在本研究中，给小鼠注射40mg/kg剂量的苯肼（PHZ），成功建立了明显的贫血动物模型，该模型导致应激性红细胞生成和铁吸收。我们发现，在最初2天血清促红细胞生成素（EPO）浓度急剧升高近5000倍，然后在注射PHZ后第6天降至基础水平。与血清EPO浓度相对应，注射PHZ后3天，骨髓和脾脏中促红细胞生成素铁调节蛋白（ERFE）的mRNA表达迅速增加，然后逐渐下降，但在第6天仍高于基线水平。此外，我们还发现，在第5天，铁调素mRNA水平几乎逐渐降低至近8倍，然后与未处理的对照组相比有所改善。机制研究表明，血清EPO的增加基本上决定了ERFE表达的诱导，特别是在PHZ处理后的前3天。慢病毒介导的ERFE敲低显著抑制了PHZ处理下铁调素的抑制。因此，我们的数据揭示了在PHZ诱导的溶血性贫血中，EPO依赖的ERFE表达作为红细胞生成驱动的铁代谢调节因子发挥作用。
