Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Life Sci Alliance. 2023 Apr 25;6(7). doi: 10.26508/lsa.202201448. Print 2023 Jul.
Retinal pigment epithelium (RPE) is essential for the survival of retinal photoreceptors. To study retinal degeneration, sodium iodate (NaIO) has been used to cause oxidative stress-induced RPE death followed by photoreceptor degeneration. However, analyses of RPE damage itself are still limited. Here, we characterized NaIO-induced RPE damage, which was divided into three regions: periphery with normal-shaped RPE, transitional zone with elongated cells, and center with severely damaged or lost RPE. Elongated cells in the transitional zone exhibited molecular characteristics of epithelial-mesenchymal transition. Central RPE was more susceptible to stresses than peripheral RPE. Under stresses, SIRT6, an NAD-dependent protein deacylase, rapidly translocated from the nucleus to the cytoplasm and colocalized with stress granule factor G3BP1, leading to nuclear SIRT6 depletion. To overcome this SIRT6 depletion, SIRT6 overexpression was induced in the nucleus in transgenic mice, which protected RPE from NaIO and partially preserved catalase expression. These results demonstrate topological differences of mouse RPE and warrant further exploring SIRT6 as a potential target for protecting RPE from oxidative stress-induced damage.
视网膜色素上皮（RPE）对于视网膜光感受器的存活至关重要。为了研究视网膜变性，人们已经使用碘酸钠（NaIO）来引起氧化应激诱导的 RPE 死亡，随后是光感受器变性。然而，对 RPE 损伤本身的分析仍然有限。在这里，我们描述了 NaIO 诱导的 RPE 损伤，它分为三个区域：具有正常形状的 RPE 的外围区、具有伸长细胞的过渡区和具有严重受损或丢失的 RPE 的中心区。过渡区的伸长细胞表现出上皮-间充质转化的分子特征。中央 RPE 比外围 RPE 更容易受到应激。在应激下，SIRT6，一种 NAD 依赖性蛋白去乙酰化酶，迅速从核转移到细胞质，并与应激颗粒因子 G3BP1 共定位，导致核 SIRT6 耗竭。为了克服这种 SIRT6 耗竭，在转基因小鼠中诱导核内 SIRT6 过表达，这可以保护 RPE 免受 NaIO 的损伤，并部分保留过氧化氢酶的表达。这些结果表明了小鼠 RPE 的拓扑差异，值得进一步探索 SIRT6 作为保护 RPE 免受氧化应激诱导损伤的潜在靶点。
