Dependence of Retinal Pigment Epithelium Integrity on the NRF2-Heme Oxygenase-1 Axis.
Dependence of Retinal Pigment Epithelium Integrity on the NRF2-Heme Oxygenase-1 Axis.
复制标题
视网膜色素上皮完整性对NRF 2-血红素加氧酶-1轴的依赖性。
DOI：
10.1167/iovs.63.9.30
复制
发表时间：
2022-08-02
影响因子：
4.4
通讯作者：
中科院分区：
文献类型：
--
作者：
紧密连接（TJ）形成视网膜色素上皮（RPE）屏障功能的结构基础。虽然氧化应激导致年龄相关性黄斑变性，但目前尚不清楚氧化还原平衡如何控制RPE TJ完整性。在这项研究中，我们研究了核因子红细胞2相关因子2（NRF 2），转录因子，血红素加氧酶-1（HO 1），血红素降解酶编码的NRF 2靶基因HMOX 1的保护作用。ARPE 19细胞培养物和小鼠，包括野生型、Nrf 2 −/−和RPE特异性NRF 2缺陷小鼠，用施加氧化应激或影响血红素代谢的化学物质处理。此外，ARPE 19细胞中的NRF 2和HO 1表达被siRNA敲低。通过对来自小鼠的培养细胞或平板RPE组织进行抗闭锁小带-1染色来检查TJ完整性。通过ARPE 19细胞的跨膜电阻和眼组织切片中白蛋白或葡聚糖的免疫荧光染色来评估RPE屏障功能。TJ结构和RPE屏障功能受到损害，由于氧化剂暴露和NRF 2缺乏，但被救出HO 1诱导剂。此外，用HO 1抑制剂或血红素前体处理对TJ结构和RPE屏障性能是破坏性的。有趣的是，NRF 2和HO 1都在氧化应激下上调，可能是作为一种适应性反应，以减轻氧化剂造成的损害。我们的数据表明，NRF 2-HO 1轴保护TJ的完整性和RPE屏障功能的驱动血红素降解。
Tight junctions (TJs) form the structural basis of retinal pigment epithelium (RPE) barrier functions. Although oxidative stress contributes to age-related macular degeneration, it is unclear how RPE TJ integrity is controlled by redox balance. In this study, we investigated the protective roles of nuclear factor erythroid 2–related factor 2 (NRF2), a transcription factor, and heme oxygenase-1 (HO1), a heme-degrading enzyme encoded by the NRF2 target gene HMOX1. ARPE19 cell cultures and mice, including wild-type, Nrf2−/−, and RPE-specific NRF2-deficient mice, were treated with chemicals that impose oxidative stress or impact heme metabolism. In addition, NRF2 and HO1 expression in ARPE19 cells was knocked down by siRNA. TJ integrity was examined by anti–zonula occludens-1 staining of cultured cells or flatmount RPE tissues from mice. RPE barrier functions were evaluated by transepithelium electrical resistance in ARPE19 cells and immunofluorescence staining for albumin or dextran in eye histological sections. TJ structures and RPE barrier functions were compromised due to oxidant exposure and NRF2 deficiency but were rescued by HO1 inducer. Furthermore, treatment with HO1 inhibitor or heme precursor is destructive to TJ structures and RPE barrier properties. Interestingly, both NRF2 and HO1 were upregulated under oxidative stress, probably as an adaptive response to mitigate oxidant-inflicted damages. Our data indicate that the NRF2–HO1 axis protects TJ integrity and RPE barrier functions by driving heme degradation.
登录
查看更多内容
影响因子：
4.8
作者：
Chen, XL;Varner, SE;Kunsch, C
通讯作者：
Kunsch, C
影响因子：
11.4
作者：
Chi, Yuan;Zhang, Xiling;Zhang, Zhen;Mitsui, Takahiko;Kamiyama, Manabu;Takeda, Masayuki;Yao, Jian
通讯作者：
Yao, Jian
影响因子：
7.4
作者：
Bonilha VL;Bell BA;Rayborn ME;Samuels IS;King A;Hollyfield JG;Xie C;Cai H
通讯作者：
Cai H
影响因子：
3.7
作者：
Gu X;Neric NJ;Crabb JS;Crabb JW;Bhattacharya SK;Rayborn ME;Hollyfield JG;Bonilha VL
通讯作者：
Bonilha VL
影响因子：
16.6
作者：
Benedicto I;Lehmann GL;Ginsberg M;Nolan DJ;Bareja R;Elemento O;Salfati Z;Alam NM;Prusky GT;Llanos P;Rabbany SY;Maminishkis A;Miller SS;Rafii S;Rodriguez-Boulan E
通讯作者：
Rodriguez-Boulan E