SLC4A11 depletion impairs NRF2 mediated antioxidant signaling and increases reactive oxygen species in human corneal endothelial cells during oxidative stress.
SLC4A11 depletion impairs NRF2 mediated antioxidant signaling and increases reactive oxygen species in human corneal endothelial cells during oxidative stress.
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DOI：
10.1038/s41598-017-03654-4
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发表时间：
2017-06-22
影响因子：
4.6
通讯作者：
Roy S
中科院分区：
文献类型：
--
作者：
Guha S;Chaurasia S;Ramachandran C;Roy S
角膜内皮营养不良是一种以角膜内皮细胞变性和功能障碍为特征的渐进性疾病，其视力逐渐丧失。钠离子依赖性OH−转运蛋白SLC4A11的突变会导致先天性遗传性内皮营养不良（CHED）和富克斯内皮角膜营养不良（FECD），这是两种最常见的内皮变性形式。沿着遗传因素，氧化应激在多种角膜疾病的发病机制中发挥作用。在这项研究中，我们研究了SLC4A11在人角膜内皮细胞（HCEnC）抗氧化应激反应中的作用。我们发现在氧化应激的存在下SLC4A11的表达增加。使用靶向siRNA耗尽SLC4A11导致活性氧物质、细胞色素c增加，线粒体膜电位降低，并在氧化应激期间降低细胞活力。此外，SLC4A11被发现是必需的NRF2介导的抗氧化基因的表达在HCEnC。另一方面，SLC4A11的过表达降低了活性氧水平并增加了细胞活力。最后，CHED组织标本显示氧化应激和NRF2表达减少的证据。总之，我们的数据表明，SLC4A11在调节氧化应激中的可能作用，并可能负责角膜内皮营养不良的病因和治疗。
Corneal endothelial dystrophy is a progressive disease with gradual loss of vision and characterized by degeneration and dysfunction of corneal endothelial cells. Mutations in SLC4A11, a Na+ dependent OH− transporter, cause congenital hereditary endothelial dystrophy (CHED) and Fuchs’ endothelial corneal dystrophy (FECD), the two most common forms of endothelial degeneration. Along with genetic factors, oxidative stress plays a role in pathogenesis of several corneal diseases. In this study we looked into the role of SLC4A11 in antioxidant stress response in human corneal endothelial cells (HCEnC). We found increased expression of SLC4A11 in presence of oxidative stress. Depletion of SLC4A11 using targeted siRNA, caused an increase in reactive oxygen species, cytochrome c, lowered mitochondrial membrane potential, and reduced cell viability during oxidative stress. Moreover, SLC4A11 was found to be necessary for NRF2 mediated antioxidant gene expression in HCEnC. On the other hand, over expression of SLC4A11 reduces reactive oxygen species levels and increases cell viability. Lastly, CHED tissue specimens show evidence of oxidative stress and reduced expression of NRF2. In conclusion, our data suggests a possible role of SLC4A11 in regulating oxidative stress, and might be responsible for both the etiology and treatment of corneal endothelial dystrophy.