Ribeiro Sandra, Garrido Patrícia, Fernandes João, Rocha Susana, Rocha-Pereira Petronila, Costa Elísio, Belo Luís, Reis Flávio, Santos-Silva Alice
Research Unit on Applied Molecular Biosciences (UCIBIO), REQUIMTE, Department of Biological Sciences, Laboratory of Biochemistry, Faculty of Pharmacy, University of Porto, Porto, Portugal.
Laboratory of Pharmacology & Experimental Therapeutics, Institute for Biomedical Imaging and Life Sciences (IBILI), Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
Blood Cells Mol Dis. 2016 Jul;59:63-70. doi: 10.1016/j.bcmd.2016.04.008. Epub 2016 Apr 19.
The crosstalk between several factors controlling hepcidin synthesis is poorly clarified for different physiological and pathological conditions. Our aim was to study the impact of increasing recombinant human erythropoietin (rHuEPO) doses on erythropoiesis, iron metabolism and hepcidin, using a rat model. Male Wistar rats were divided in 5 groups: control (vehicle) and rHuEPO-treated groups (100, 200, 400 and 600IU/kgbody weight/week), 3 times per week, during 3weeks. Hematological and iron data were evaluated. The expression of several genes involved in iron metabolism was analyzed by qPCR. Liver hepcidin protein was evaluated by Western Blot. The rHuEPO treatment induced erythropoiesis and increased transferrin saturation (TSAT) in a dose dependent manner. Tf receptor 2 (TfR2), hemojuvelin (HJV) and bone morphogenetic protein 6 (BMP6) were up-regulated in rHuEPO200 group. Matriptase-2 was down-regulated in rHuEPO200 group, and up-regulated in the other rHuEPO-treated groups. Hepcidin synthesis was increased in rHuEPO200 group, and repressed in the rHuEPO400 and rHuEPO600 groups. Our study showed that when a high erythropoietic stimulus occurs, hepcidin synthesis is mainly regulated by TSAT; however, when the erythropoiesis rate reaches a specific threshold, extramedullary hematopoiesis is triggered, and the control of hepcidin synthesis is switched to matriptase-2, thus inhibiting hepcidin synthesis.
在不同的生理和病理条件下，控制铁调素合成的几个因素之间的相互作用尚不清楚。我们的目的是使用大鼠模型研究增加重组人促红细胞生成素（rHuEPO）剂量对红细胞生成、铁代谢和铁调素的影响。将雄性Wistar大鼠分为5组：对照组（赋形剂）和rHuEPO治疗组（100、200、400和600IU/kg体重/周），每周3次，共3周。评估血液学和铁数据。通过qPCR分析参与铁代谢的几个基因的表达。通过蛋白质印迹法评估肝脏铁调素蛋白。rHuEPO治疗以剂量依赖性方式诱导红细胞生成并增加转铁蛋白饱和度（TSAT）。rHuEPO200组中，转铁蛋白受体2（TfR2）、血色素沉着症相关蛋白（HJV）和骨形态发生蛋白6（BMP6）上调。rHuEPO200组中，Matriptase-2下调，而在其他rHuEPO治疗组中上调。rHuEPO200组中铁调素合成增加，而在rHuEPO400和rHuEPO600组中受到抑制。我们的研究表明，当发生高红细胞生成刺激时，铁调素合成主要受TSAT调节；然而，当红细胞生成率达到特定阈值时，会触发髓外造血，铁调素合成的控制则切换至Matriptase-2，从而抑制铁调素合成。
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