PURPOSE Obesity is a global health problem associated with several diseases including ocular complications. Earlier we reported progressive retinal degeneration because of obesity in a spontaneous obese rat (WNIN/Ob) model. In the current study, we examined the molecular mechanisms leading to retinal degeneration in WNIN/Ob rat. METHODS Sorbitol was estimated by the fluorometric method in the retina of WNIN/Ob rats at different age (3-, 6- and 12- months), along with their respective lean rats. Immunoblotting was performed in the retina to assess the status of the insulin signaling pathway, ER stress and cellular stress (p38MAPK and ERK1/2). Human SK-N-SH cells were treated with 0.5 and 1.0 M sorbitol for 30 min to study insulin signaling, ER stress, and cellular stress. TUNEL assay was done to measure apoptosis. The retinal function in the rats was determined by electroretinogram. RESULTS A gradual but significantly higher intracellular sorbitol accumulation was observed in the retina of obese rats from 3- to 12-months. The cellular osmotic stress has activated the insulin signaling mechanism without activating AKT and also triggered ER stress. Both the stresses activated the ERK and p38MAPK signaling causing apoptosis in the retina leading to retinal degeneration. Retinal dysfunction was confirmed by altered scotopic and photopic electroretinogram responses. These in vivo results were mimicked in SK-N-SH cells when exposed to sorbitol in vitro. CONCLUSIONS These results suggest cellular stress due to sorbitol accumulation impairing the ER function, thereby leading to progressive retinal degeneration under obese conditions.

中文翻译：

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山梨醇介导的细胞应激反应在肥胖相关视网膜变性中的作用。

目的肥胖是一个全球性的健康问题，与包括眼部并发症在内的多种疾病有关。早些时候，我们报道了自发性肥胖大鼠 (WNIN/Ob) 模型中因肥胖导致的进行性视网膜变性。在当前的研究中，我们检查了导致 WNIN/Ob 大鼠视网膜变性的分子机制。方法 在不同年龄（3、6 和 12 个月）的 WNIN/Ob 大鼠及其各自的瘦大鼠的视网膜中，通过荧光法评估山梨糖醇。在视网膜中进行免疫印迹以评估胰岛素信号通路、ER 应激和细胞应激（p38MAPK 和 ERK1/2）的状态。人 SK-N-SH 细胞用 0.5 和 1.0 M 山梨糖醇处理 30 分钟，以研究胰岛素信号、ER 应激和细胞应激。进行 TUNEL 测定以测量细胞凋亡。通过视网膜电图确定大鼠的视网膜功能。结果 在 3 至 12 个月大的肥胖大鼠的视网膜中观察到逐渐但显着更高的细胞内山梨糖醇积累。细胞渗透压激活了胰岛素信号机制而不激活 AKT，并且还触发了 ER 压力。这两种压力都激活了 ERK 和 p38MAPK 信号，导致视网膜细胞凋亡，导致视网膜变性。通过改变的暗视和明视视网膜电图反应证实了视网膜功能障碍。当体外暴露于山梨糖醇时，这些体内结果在 SK-N-SH 细胞中被模拟。结论 这些结果表明，由于山梨糖醇积累会损害 ER 功能，从而导致细胞应激，从而导致肥胖条件下进行性视网膜变性。