HDAC3 抑制通过抑制炎症小体激活减轻高糖诱导的视网膜神经节细胞死亡。
HDAC3 Inhibition Alleviates High-Glucose-Induced Retinal Ganglion Cell Death through Inhibiting Inflammasome Activation.
机构信息
Kunshan First People's Hospital of Kunshan Affiliated with Jiangsu University, Suzhou, Jiangsu 215300, China.
Department of Neurology, Kunshan First People's Hospital Affiliated to Jiangsu University, Suzhou, Jiangsu 215300, China.
出版信息
Biomed Res Int. 2022 Aug 21;2022:4164824. doi: 10.1155/2022/4164824. eCollection 2022.
PURPOSE
The exact effects of histone deacetylase 3 (HDAC3) inhibition in DR related retinal ganglion cells (RGCs) death remained unclear. This study is aimed at detecting the influence of HDAC3 on the high-glucose-induced retinal ganglion cell death.
METHODS
The retinal HDAC3 expression in DR of different time points was analyzed by immunohistochemical assay and western blot. Besides, the expression of HDAC3 and both retinal thickness and RGC loss were analyzed. The effects of HDAC3 inhibitor on cell viability, oxidative stress, and apoptosis in high-glucose- (HG-) treated RGCs were analyzed. Both inflammatory and antioxidative factors were detected by ELISA.
RESULTS
Advanced effects of HDAC3 inhibition on the expression of NLRP3 inflammasome were detected using western blots. High HDAC3 expression was detected only in the late DR mice (4 months of diabetes duration) but not early DR mice (2 months of diabetes duration). The immunohistochemical assay showed that HDAC3 expression was correlated with both retinal thickness and RCG contents. HDAC3 inhibitor significantly protected the HG-treated RGCs from damaged cell viability, severe apoptosis, and oxidative stress. Advanced pathway analyses showed that HDAC3 inhibition inactivated NLRP3 inflammasome and thus alleviated retinal inflammation. In conclusion, HDAC3 was involved in RGC loss and thus promoted the progression of neurodegeneration of DR. Besides, HDAC3 inhibitor demonstrated protective effects in neurodegeneration in DR through downregulation of NLRP3 activity. The effects of HDAC3 inhibitor in DR management should be confirmed in clinical trials.
目的
组蛋白去乙酰化酶 3（HDAC3）抑制在 DR 相关的视网膜神经节细胞（RGC）死亡中的确切作用仍不清楚。本研究旨在检测 HDAC3 对高糖诱导的视网膜神经节细胞死亡的影响。
方法
通过免疫组织化学和 Western blot 分析 DR 不同时间点的视网膜 HDAC3 表达。此外，还分析了 HDAC3 的表达以及视网膜厚度和 RGC 损失。分析了 HDAC3 抑制剂对高糖（HG）处理的 RGC 中细胞活力、氧化应激和细胞凋亡的影响。通过 ELISA 检测炎症和抗氧化因子。
结果
Western blot 检测到 HDAC3 抑制对 NLRP3 炎性小体表达的晚期作用。仅在晚期 DR 小鼠（糖尿病病程 4 个月）中检测到高 HDAC3 表达，而在早期 DR 小鼠（糖尿病病程 2 个月）中未检测到。免疫组织化学检测显示 HDAC3 表达与视网膜厚度和 RCG 含量均相关。HDAC3 抑制剂显著保护 HG 处理的 RGC 免受受损的细胞活力、严重的细胞凋亡和氧化应激。高级通路分析表明，HDAC3 抑制使 NLRP3 炎性小体失活，从而减轻视网膜炎症。总之，HDAC3 参与 RGC 丢失，从而促进 DR 神经退行性变的进展。此外，HDAC3 抑制剂通过下调 NLRP3 活性在 DR 神经退行性变中显示出保护作用。HDAC3 抑制剂在 DR 管理中的作用应在临床试验中得到证实。
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