Hepcidin Suppresses Brain Iron Accumulation by Downregulating Iron Transport Proteins in Iron-Overloaded Rats
Hepcidin Suppresses Brain Iron Accumulation by Downregulating Iron Transport Proteins in Iron-Overloaded Rats
复制标题
铁调素通过下调铁超载大鼠的铁转运蛋白来抑制脑铁积累
DOI：
10.1007/s12035-014-8847-x
复制
发表时间：
2015-08-01
影响因子：
5.1
通讯作者：
Ke, Ya
中科院分区：
文献类型：
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作者：
Du, Fang;Qian, Zhong-Ming;Ke, Ya
随着年龄的增长，铁在大脑中逐渐积累，铁诱导的氧化应激被认为是阿尔茨海默病（AD）和帕金森病（PD）的最初原因之一。基于铁调素在外周器官中的作用及其在大脑中的表达，我们假设这种肽具有减少大脑中铁的作用，因此有可能预防或延迟铁相关神经退行性疾病中脑铁的积累。在这里，我们研究了铁调素表达腺病毒（ad-hepcidin）和铁调素肽对培养的微血管内皮细胞中脑铁含量、铁跨脑血屏障转运、铁摄取和释放以及转铁蛋白受体1（TfR1）、二价金属转运蛋白1（DMT1）和铁转运蛋白1（Fpn1）表达的影响，以及 神经元。我们证明，铁调素可显着减少铁超载大鼠的脑铁含量，并抑制转铁蛋白结合铁（Tf-Fe）从外周转运至大脑。此外，该肽显着抑制培养的微血管内皮细胞和神经元中 TfR1、DMT1 和 Fpn1 的表达，并减少 Tf-Fe 和非转铁蛋白结合的铁吸收和铁释放，而铁调素 siRNA 逆转录病毒下调铁调素则产生相反的结果。我们得出的结论是，在铁过载的情况下，铁调素通过下调铁转运蛋白来减少大脑中的铁。 Ad-hepcidin 上调脑铁调素成为铁相关神经退行性疾病的一种新的药物治疗和预防方法。
Iron accumulates progressively in the brain with age, and iron-induced oxidative stress has been considered as one of the initial causes for Alzheimer's disease (AD) and Parkinson's disease (PD). Based on the role of hepcidin in peripheral organs and its expression in the brain, we hypothesized that this peptide has a role to reduce iron in the brain and hence has the potential to prevent or delay brain iron accumulation in iron-associated neurodegenerative disorders. Here, we investigated the effects of hepcidin expression adenovirus (ad-hepcidin) and hepcidin peptide on brain iron contents, iron transport across the brain-blood barrier, iron uptake and release, and also the expression of transferrin receptor-1 (TfR1), divalent metal transporter 1 (DMT1), and ferroportin 1 (Fpn1) in cultured microvascular endothelial cells and neurons. We demonstrated that hepcidin significantly reduced brain iron in iron-overloaded rats and suppressed transport of transferrin-bound iron (Tf-Fe) from the periphery into the brain. Also, the peptide significantly inhibited expression of TfR1, DMT1, and Fpn1 as well as reduced Tf-Fe and non-transferrin-bound iron uptake and iron release in cultured microvascular endothelial cells and neurons, while downregulation of hepcidin with hepcidin siRNA retrovirus generated opposite results. We concluded that, under iron-overload, hepcidin functions to reduce iron in the brain by downregulating iron transport proteins. Upregulation of brain hepcidin by ad-hepcidin emerges as a new pharmacological treatment and prevention for iron-associated neurodegenerative disorders.