Constitutive overexpression of human erythropoietin protects the mouse retina against induced but not inherited retinal degeneration
Constitutive overexpression of human erythropoietin protects the mouse retina against induced but not inherited retinal degeneration
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DOI：
10.1523/jneurosci.1288-04.2004
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发表时间：
2004-06-23
影响因子：
5.3
通讯作者：
Remé, C
中科院分区：
文献类型：
--
作者：
Grimm, C;Wenzel, A;Remé, C
低氧预处理或应用重组人促红细胞生成素（huEpo）提高促红细胞生成素（Epo）浓度可通过抑制光感受器细胞凋亡保护小鼠视网膜免受光诱导的变性。由于感光细胞凋亡也是视网膜营养不良如视网膜色素变性（RP）中细胞损失的常见途径，我们测试了高水平的huEpo是否会减少两种人RP小鼠模型中的凋亡性细胞死亡。我们将两个相应的突变小鼠品系与主要在神经组织中组成型过表达huEpo的转基因品系（tg 6）组合。huEpo的转基因表达引起视网膜中组成性高水平的Epo，并保护光感受器免受光诱导的变性;然而，高水平huEpo的存在并不影响光非依赖性（rd 1）和光加速（VPP）RP小鼠模型中视网膜变性的过程或程度。类似地，重复腹膜内注射重组huEpo不能保护rd 1和VPP小鼠的视网膜。在两种遗传性视网膜变性模型中缺乏Epo的神经保护作用不是由Epo受体的适应性下调引起的。我们的研究结果表明，在急性光诱导的感光细胞死亡的凋亡机制不同于那些遗传性视网膜变性。因此，对遗传性视网膜变性中细胞死亡的治疗性干预可能需要不同的药物和治疗。
Elevation of erythropoietin (Epo) concentrations by hypoxic preconditioning or application of recombinanthuman Epo (huEpo) protects the mouse retina against light-induced degeneration by inhibiting photoreceptor cell apoptosis. Because photoreceptor apoptosis is also the common path to cell loss in retinal dystrophies such as retinitis pigmentosa ( RP), we tested whether high levels of huEpo would reduce apoptotic cell death in two mouse models of human RP. We combined the two respective mutant mouse lines with a transgenic line (tg6) that constitutively overexpresses huEpo mainly in neural tissues. Transgenic expression of huEpo caused constitutively high levels of Epo in the retina and protected photoreceptors against light-induced degeneration; however, the presence of high levels of huEpo did not affect the course or the extent of retinal degeneration in a light-independent (rd1) and a light-accelerated (VPP) mouse model of RP. Similarly, repetitive intraperitoneal injections of recombinant huEpo did not protect the retina in the rd1 and the VPP mouse. Lack of neuroprotection by Epo in the two models of inherited retinal degeneration was not caused by adaptational downregulation of Epo receptor. Our results suggest that apoptotic mechanisms during acute, light-induced photoreceptor cell death differ from those in genetically based retinal degeneration. Therapeutic intervention with cell death in inherited retinal degeneration may therefore require different drugs and treatments.