Epigenetic modifications of Nrf2-mediated glutamate-cysteine ligase: implications for the development of diabetic retinopathy and the metabolic memory phenomenon associated with its continued progression.
Epigenetic modifications of Nrf2-mediated glutamate-cysteine ligase: implications for the development of diabetic retinopathy and the metabolic memory phenomenon associated with its continued progression.
复制标题
DOI：
10.1016/j.freeradbiomed.2014.07.001
复制
发表时间：
2014-10
影响因子：
7.4
通讯作者：
Kowluru, Renu A.
中科院分区：
文献类型：
--
作者：
Mishra, Manish;Zhong, Qing;Kowluru, Renu A.
关键词：
糖尿病会增加视网膜的氧化应激，并降低细胞内抗氧化剂谷胱甘肽（GSH）的水平。转录因子 Nrf2 调节 Gclc 的表达，Gclc 是 GSH 生物合成中重要的酶，在糖尿病中，Nrf2 在抗氧化反应元件区域 4 (ARE4) 上的结合减少。我们的目的是研究表观遗传修饰在 Gclc-ARE4 上 Nrf2 结合减少的过程中在糖尿病视网膜病变的发展以及与其持续进展相关的代谢记忆中的作用。通过大鼠视网膜染色质免疫沉淀研究高血糖对 Nrf2 与 Gclc-ARE4 结合的 H3K4 甲基化的影响，并在操纵组蛋白去甲基化酶 (LSD1) 的视网膜内皮细胞中得到证实。在维持不良控制 3 个月，然后维持良好控制 (GC) 3 个月的大鼠中，检查了 Gclc-ARE4 组蛋白甲基化在代谢记忆中的作用。尽管 Gclc-ARE4 上的 H3K4me2 在糖尿病中增加，但 H3K4me3 和 H3K4me1 减少。 LSD1 siRNA 消除了葡萄糖诱导的 Gclc-ARE4 上 H3K4me1 的减少，并改善了 Gclc-ARE4 和 Gclc 转录本上 Nrf2 结合的减少。 GC 的重建未能为组蛋白甲基化提供任何益处，并且 Nrf2 结合活性仍然受到损害。因此，在糖尿病视网膜病变中，Gclc-ARE4 的组蛋白甲基化在调节 Nrf2-Gclc-GSH 级联中发挥着重要作用。针对组蛋白甲基化可以帮助抑制/减缓这种致盲疾病。
Diabetes increases oxidative stress in the retina and decreases the levels of the intracellular antioxidant glutathione (GSH). The transcriptional factor Nrf2 regulates the expression of Gclc, the enzyme important in the biosynthesis of GSH, and in diabetes the binding of Nrf2 at the antioxidant response element region 4 (ARE4) is decreased. Our aim was to investigate the role of epigenetic modifications in the decreased Nrf2 binding at Gclc-ARE4 in the development of diabetic retinopathy and in the metabolic memory associated with its continued progression. The effect of hyperglycemia on H3K4 methylation in Nrf2 binding at Gclc-ARE4 was investigated by chromatin immunoprecipitation in the rat retina and was confirmed in retinal endothelial cells in which histone demethylase (LSD1) was manipulated. The role of histone methylation at Gclc-ARE4 in the metabolic memory was examined in rats maintained under poor control for 3 months followed by good control (GC) for 3 months. Although H3K4me2 at Gclc-ARE4 was increased in diabetes, H3K4me3 and H3K4me1 were decreased. LSD1 siRNA abrogated the glucose-induced decrease in H3K4me1 at Gclc-ARE4 and ameliorated decreases in Nrf2 binding at Gclc-ARE4 and Gclc transcripts. Reestablishment of GC failed to provide any benefits to histone methylation, and Nrf2 binding activity remained compromised. Thus, in diabetic retinopathy, histone methylation at Gclc-ARE4 plays an important role in regulating the Nrf2–Gclc–GSH cascade. Targeting histone methylation could help inhibit/slow down this blinding disease.
登录
查看更多内容
影响因子：
64.5
作者：
Kaelin WG Jr;McKnight SL
通讯作者：
McKnight SL
糖尿病的代谢记忆 - 从体外奇怪到体内问题：凋亡的作用。
影响因子：
3.8
作者：
Kowluru, Renu A.;Chan, Pooi-See
通讯作者：
Chan, Pooi-See
影响因子：
4.8
作者：
Erickson, AM;Nevarea, Z;Mulcahy, RT
通讯作者：
Mulcahy, RT
影响因子：
7.7
作者：
Kowluru, RA
通讯作者：
Kowluru, RA
影响因子：
3
作者：
Lu, Shelly C.
通讯作者：
Lu, Shelly C.