Iron-mediated retinal degeneration in haemojuvelin-knockout mice.
Iron-mediated retinal degeneration in haemojuvelin-knockout mice.
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铁介导的小鼠介导的视网膜变性。
DOI：
10.1042/bj20111148
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发表时间：
2012-01-15
期刊：
影响因子：
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通讯作者：
Ganapathy V
中科院分区：
文献类型：
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作者：
Gnana-Prakasam JP;Tawfik A;Romej M;Ananth S;Martin PM;Smith SB;Ganapathy V
血色素沉着症是一种铁超载的遗传性疾病，由铁调节蛋白HFE、转铁蛋白受体2、铁转运蛋白、hepcidin和血红蛋白（HJV）编码基因的功能缺失突变引起。最近的研究已经确定了这五种基因在视网膜中的表达，表明它们在视网膜铁稳态中的重要性。我们之前已经证明Hjv在视网膜色素上皮（RPE）、外核层和内核层以及神经节细胞层中表达。在这里，我们报道了Hjv缺失对小鼠视网膜的影响。与年龄匹配的对照组相比，≥18月龄的Hjv-null小鼠视网膜铁积累增加，形态学损伤明显；这些变化在年轻的老鼠身上没有发现。Hjv-null小鼠的视网膜表型为RPE增生。我们从野生型和Hjv-null小鼠中分离RPE细胞，观察其生长模式。Hjv-null RPE细胞衰老程度较低，表现出超增殖表型。Hjv-null RPE细胞也表现出编码异二聚体氨基酸转运体胱氨酸/谷氨酸交换体（xCT/4F2hc）中“转运体适当”亚基xCT的Slc7a11的上调。骨形态发生蛋白（Bone morphogenic protein， BMP） 6在Hjv-null RPE细胞中不能诱导hepcidin的表达，证实视网膜细胞需要Hjv通过BMP6信号传导诱导hepcidin。Hjv是一种糖基磷脂酰肌醇锚定蛋白，膜相关的Hjv是RPE细胞中bmp6介导的hepcidin启动子激活所必需的。综上所述，这些研究证实了Hjv在视网膜和RPE中铁稳态调节中的生物学重要性。
Hemochromatosis is a genetic disorder of iron overload resulting from loss-of-function mutations in genes coding for the iron-regulatory proteins HFE, transferrin receptor 2, ferroportin, hepcidin, and hemojuvelin (HJV). Recent studies have established the expression of all the five genes in retina, indicating their importance in retinal iron homeostasis. We previously demonstrated that Hjv is expressed in retinal pigment epithelium (RPE), outer and inner nuclear layers, and ganglion cell layer. Here we report on the consequences of Hjv deletion on the retina in mice. Hjv-null mice at ≥ 18 months of age had increased iron accumulation in retina with marked morphological damage compared to age-matched controls; these changes were not found in younger mice. The retinal phenotype in Hjv-null mice included hyperplasia of RPE. We isolated RPE cells from wild type and Hjv-null mice and examined their growth patterns. Hjv-null RPE cells were less senescent and exhibited a hyperproliferative phenotype. Hjv-null RPE cells also showed upregulation of Slc7a11 that codes for the ‘transporter proper’ subunit xCT in the heterodimeric amino acid transporter cystine/glutamate exchanger (xCT/4F2hc). Bone morphogenic protein (BMP) 6 could not induce hepcidin expression in Hjv-null RPE cells, confirming that retinal cells require Hjv for induction of hepcidin via BMP6 signaling. Hjv is a glycosylphosphatidylinositol-anchored protein, and the membrane-associated Hjv is necessary for BMP6-mediated activation of hepcidin promoter in RPE cells. Taken together, these studies confirm the biological importance of Hjv in the regulation of iron homeostasis in the retina and in RPE.