Taskintuna Kaan, Bhat Mohd Akbar, Shaikh Tasneem, Hum Jacob, Golestaneh Nady
Department of Ophthalmology, Georgetown University Medical Center, Washington, DC, United States.
Department of Pharmacology and Physiology, Georgetown University Medical Center, Washington, DC, United States.
Front Cell Neurosci. 2024 Sep 2;18:1442079. doi: 10.3389/fncel.2024.1442079. eCollection 2024.
Age-related macular degeneration (AMD) is a major cause of blindness that affects people over 60. While aging is the prominent factor in AMD, studies have reported a higher prevalence of AMD in women compared to age-matched men. Higher levels of the innate immune response's effector proteins complement factor B and factor I were also found in females compared to males in intermediate AMD. However, the mechanisms underlying these differences remain elusive. Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) is a key regulator of mitochondrial biogenesis and metabolic pathways. Previously, we showed that repression and high-fat diet induce drastic AMD-like phenotypes in mice. Our recent data revealed that repression alone can also induce retinal pigment epithelium (RPE) and retinal dysfunction in mice, and its inhibition results in lipid droplet accumulation in human RPE. Whether sex is a contributing factor in these phenotypes remains to be elucidated. Using electroretinography, we demonstrate that sex could influence RPE function during aging independent of in wild-type (WT) mice. We further show that repression exacerbates RPE and retinal dysfunction in females compared to aged-match male mice. Gene expression analyses revealed that differentially regulates genes related to antioxidant enzymes and mitochondrial dynamics in males and females. RPE flat mounts immunolabeled with TOMM20 and DRP1 indicated a sex-dependent role for in regulating mitochondrial fission. Analyses of mitochondrial network morphology suggested sex-dependent effects of repression on mitochondrial dynamics. Together, our study demonstrates that inhibition of induces a sex-dependent decline in RPE and retinal function in mice. These observations on the sex-dependent regulation of RPE and retinal function could offer novel insights into targeted therapeutic approaches for age-related RPE and retinal degeneration.
年龄相关性黄斑变性（AMD）是导致60岁以上人群失明的主要原因。虽然衰老在AMD中是一个突出因素，但研究报告称，与年龄匹配的男性相比，AMD在女性中的患病率更高。在中度AMD患者中，女性体内天然免疫反应的效应蛋白补体因子B和因子I的水平也高于男性。然而，这些差异背后的机制仍然难以捉摸。过氧化物酶体增殖物激活受体γ共激活因子-1α（PGC-1α）是线粒体生物发生和代谢途径的关键调节因子。此前，我们发现抑制和高脂饮食会在小鼠中诱导出严重的AMD样表型。我们最近的数据显示，单独抑制也会在小鼠中诱导视网膜色素上皮（RPE）和视网膜功能障碍，而抑制其活性会导致人RPE中脂滴积累。性别是否是这些表型的一个影响因素仍有待阐明。通过视网膜电图检查，我们证明在野生型（WT）小鼠中，性别可独立于衰老过程影响RPE功能。我们进一步表明，与年龄匹配的雄性小鼠相比，抑制会加剧雌性小鼠的RPE和视网膜功能障碍。基因表达分析表明，抑制在雄性和雌性小鼠中对与抗氧化酶和线粒体动力学相关的基因有不同的调节作用。用TOMM20和DRP1进行免疫标记的RPE平铺片显示，抑制在调节线粒体分裂中具有性别依赖性作用。线粒体网络形态分析表明，抑制对线粒体动力学有性别依赖性影响。总之，我们的研究表明，抑制会在小鼠中诱导RPE和视网膜功能出现性别依赖性下降。这些关于RPE和视网膜功能性别依赖性调节的观察结果可能为年龄相关性RPE和视网膜变性的靶向治疗方法提供新的见解。
