Mice with hepcidin-resistant ferroportin accumulate iron in the retina
Mice with hepcidin-resistant ferroportin accumulate iron in the retina
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DOI：
10.1096/fj.15-276758
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发表时间：
2016-02-01
期刊：
影响因子：
4.8
通讯作者：
Dunaief, Joshua L.
中科院分区：
文献类型：
--
作者：
Theurl, Milan;Song, Delu;Dunaief, Joshua L.
由于膜铁转运蛋白（ferroportin，Fpn）是哺乳动物细胞中唯一已知的铁输出蛋白，了解其在视网膜中的定位和调控将有助于了解视网膜铁通量的方向。激素铁调素可以调节视网膜Fpn，因为它触发肠道中的Fpn降解。使用免疫荧光标记具有4种不同基因型（野生型; Fpn C326 S，铁调素抗性Fpn;铁调素敲除;和血浆铜蓝蛋白/铁蛋白双敲除）的小鼠视网膜中的Fpn。在这些视网膜中未观察到Fpn水平的显著差异。Fpn定位于外丛状血管内皮细胞、Muller胶质细胞的近腔侧和视网膜色素上皮的基底外侧。将腺相关病毒（AAV）-铁调素注射到铁调素敲除小鼠的眼中，而将AAV-lacZ注射到对侧眼中作为对照。注射AAV-铁调素的眼睛在视网膜血管内皮细胞中具有增加的铁蛋白免疫标记。与野生型相比，Fpn C326 S小鼠具有全身性铁过载，并且具有迄今为止研究的任何遗传模型中最快的视网膜铁积累。结果表明，生理铁调素水平不足以改变视网膜色素上皮和穆勒细胞内的Fpn水平，但可能会限制铁从血管内皮细胞转运到视网膜中。
Because ferroportin (Fpn) is theonlyknown mammalian cellular iron exporter, understanding its localization and regulation within the retina would shed light on the direction of retinal iron flux. The hormone hepcidin may regulate retinal Fpn, as it triggers Fpn degradation in the gut. Immunofluorescence was used to label Fpn in retinas of mice with 4 different genotypes (wild type; Fpn C326S, a hepcidin-resistant Fpn; hepcidin knockout; and ceruloplasmin/hephaestin double knockout). No significant difference in Fpn levels was observed in these retinas. Fpn localized to the abluminal side of the outer plexiform vascular endothelial cells, Muller glia cells, and the basolateral side of the retinal pigment epithelium. Adeno-associated virus (AAV)-hepcidin was injected into the eyes of hepcidin knockout mice, while AAV-lacZ was injected into the contralateral eyes as a control. AAV-hepcidin injected eyes had increased ferritin immunolabeling in retinal vascular endothelial cells. Fpn C326S mice had systemic iron overload compared to wild type and had the fastest retinal iron accumulation of any hereditary model studied to date. The results suggest that physiologic hepcidin levels are insufficient to alter Fpn levels within the retinal pigment epithelium and Muller cells, but may limit iron transport into the retina from vascular endothelial cells.