Department of Medicine, Endocrinology, and Diabetes, Harold Hamm Oklahoma Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
Diabetes. 2012 Feb;61(2):492-504. doi: 10.2337/db11-0315. Epub 2012 Jan 6.
Inflammation plays an important role in diabetes-induced retinal vascular leakage. The purpose of this study is to examine the role of endoplasmic reticulum (ER) stress and the signaling pathway of ER stress-induced activating transcription factor 4 (ATF4) in the regulation of Müller cell-derived inflammatory mediators in diabetic retinopathy. In diabetic animals, elevated ER stress markers, ATF4, and vascular endothelial growth factor (VEGF) expression were partially localized to Müller cells in the retina. In cultured Müller cells, high glucose induced a time-dependent increase of ER stress, ATF4 expression, and inflammatory factor production. Inducing ER stress or overexpressing ATF4 resulted in elevated intracellular adhesion molecule 1 and VEGF proteins in Müller cells. In contrast, alleviation of ER stress or blockade of ATF4 activity attenuated inflammatory gene expression induced by high glucose or hypoxia. Furthermore, we found that ATF4 regulated the c-Jun NH2-terminal kinase pathway resulting in VEGF upregulation. ATF4 was also required for ER stress-induced and hypoxia-inducible factor-1α activation. Finally, we showed that administration of chemical chaperone 4-phenylbutyrate or genetic inhibition of ATF4 successfully attenuated retinal VEGF expression and reduced vascular leakage in mice with STZ-induced diabetes. Taken together, our data indicate that ER stress and ATF4 play a critical role in retinal inflammatory signaling and Müller cell-derived inflammatory cytokine production in diabetes.
在糖尿病引起的视网膜血管渗漏中，炎症起着重要作用。本研究旨在探讨内质网（ER）应激及其诱导的激活转录因子 4（ATF4）信号通路在调节糖尿病视网膜病变中 Müller 细胞源性炎症介质中的作用。在糖尿病动物中，升高的 ER 应激标志物、ATF4 和血管内皮生长因子（VEGF）表达部分定位于视网膜中的 Müller 细胞。在培养的 Müller 细胞中，高葡萄糖诱导 ER 应激、ATF4 表达和炎症因子产生的时间依赖性增加。诱导 ER 应激或过表达 ATF4 导致 Müller 细胞中细胞间黏附分子 1 和 VEGF 蛋白的升高。相反，减轻 ER 应激或阻断 ATF4 活性可减弱高葡萄糖或低氧诱导的炎症基因表达。此外，我们发现 ATF4 调节 c-Jun NH2-末端激酶途径，导致 VEGF 上调。ATF4 还需要 ER 应激诱导和缺氧诱导因子-1α 的激活。最后，我们表明，施用化学伴侣 4-苯基丁酸或遗传抑制 ATF4 可成功减轻 STZ 诱导的糖尿病小鼠的视网膜 VEGF 表达并减少血管渗漏。总之，我们的数据表明，ER 应激和 ATF4 在糖尿病中视网膜炎症信号和 Müller 细胞源性炎症细胞因子产生中起关键作用。
