Progranulin protects the mouse retina under hypoxic conditions via inhibition of the Toll‑like receptor‑4‑NADPH oxidase 4 signaling pathway.
Progranulin protects the mouse retina under hypoxic conditions via inhibition of the Toll‑like receptor‑4‑NADPH oxidase 4 signaling pathway.
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颗粒体蛋白前体通过抑制 Toll 样受体 4-NADPH 氧化酶 4 信号通路保护缺氧条件下的小鼠视网膜
DOI：
10.3892/mmr.2018.9634
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发表时间：
2019-01
影响因子：
3.4
通讯作者：
Shi K
中科院分区：
文献类型：
--
作者：
You ZP;Yu MJ;Zhang YL;Shi K
为了研究颗粒蛋白前体在缺氧条件下对视网膜的作用，将8周龄C57 BL/6小鼠分为正常条件和缺氧条件组（n=24只小鼠/组）。通过玻璃体内注射9mM氯化钴建立缺氧模型。随后，将10 mM颗粒蛋白前体和等量的PBS分别注射到右眼和左眼中。采用视网膜电图（ERG）分析检测光感受器功能。使用免疫荧光共定位检查形态学改变，使用白细胞抑制试验检查视网膜血管炎症，并使用免疫印迹筛选信号传导途径。结果表明，与正常条件下相比，在缺氧条件下的ERG振幅显着降低。此外，与前颗粒蛋白注射眼相比，PBS注射眼的振幅显著降低。形态学检查表明，在PBS注射的眼睛中的杆的数量减少相比，在缺氧条件下的progranulin注射的眼睛。此外，锥体的排列稀疏，外节的形态短而小。虽然在缺氧小鼠中，注射前颗粒蛋白的眼睛中粘附的白细胞的数量比在正常条件下的那些高，但其数量仅为注射PBS的眼睛中检测到的数量的52.31%。对信号通路的分析表明，颗粒蛋白前体对缺氧条件下视网膜的保护作用是通过Toll样受体4（TLR 4）-NADPH氧化酶4（NOX 4）通路而不是caspase和Wnt/β-catenin通路来调节的。总之，颗粒蛋白前体通过抑制TLR 4-NOX 4通路，对缺氧环境中光感受器的功能和形态具有保护作用，并可减轻视网膜血管炎症。
To investigate the function of progranulin on the retina under hypoxic conditions, 8-week-old C57BL/6 mice were divided into normal condition and hypoxic condition groups (n=24 mice/group). The hypoxia model was established through intravitreal injection of 9 mM cobalt chloride. Subsequently, 10 mM progranulin and an equal amount of PBS were injected into the right and left eyes, respectively. Photoreceptor function was examined using electroretinogram (ERG) analysis. Morphological alterations were examined using immunofluorescence co-localization, retinal vascular inflammation was examined using the leukostasis assay, and signaling pathways were screened using immunoblotting. The results revealed that ERG amplitude was significantly lower under hypoxic conditions compared with under normal conditions. Furthermore, the amplitude was significantly reduced in the PBS-injected eyes compared with in the progranulin-injected eyes. Morphological examination demonstrated that the number of rods in the PBS-injected eyes was decreased compared with in the progranulin-injected eyes under hypoxic conditions. In addition, the arrangement of the cones was sparse and the morphology of the outer segments was short and small. Although the number of adherent leukocytes in the progranulin-injected eyes was higher in the hypoxic mice compared with in those under normal conditions, the number was only 52.31% of the number detected in the PBS-injected eyes. Analysis of the signaling pathways demonstrated that the protective effects of progranulin on retinas under hypoxic conditions were regulated by the Toll-like receptor 4 (TLR4)-NADPH oxidase 4 (NOX4) pathway, instead of the caspase and Wnt/β-catenin pathways. In conclusion, progranulin exerted protective effects on the function and morphology of photoreceptors in a hypoxic environment, and could reduce retinal vascular inflammation, through inhibition of the TLR4-NOX4 pathway.
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