Elevated Activating Transcription Factor 4 and Glucose-Regulated 78 Kda Protein Levels Correlate with Inflammatory Cytokines in the Aqueous Humor and Vitreous of Proliferative Diabetic Retinopathy
Elevated Activating Transcription Factor 4 and Glucose-Regulated 78 Kda Protein Levels Correlate with Inflammatory Cytokines in the Aqueous Humor and Vitreous of Proliferative Diabetic Retinopathy
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活化转录因子 4 和葡萄糖调节的 78 Kda 蛋白水平升高与增殖性糖尿病视网膜病变房水和玻璃体中的炎症细胞因子相关
DOI：
10.1080/02713683.2017.1297998
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发表时间：
2017-01-01
影响因子：
2
通讯作者：
Shen, Xi
中科院分区：
文献类型：
--
作者：
Wang, Yanuo;Gao, Sha;Shen, Xi
摘要目的：检测增殖性糖尿病视网膜病变(PDR)患者玻璃体和房水中内质网应激相关因子激活转录因子4(ATF4)和葡萄糖调节78 kDa蛋白(GRP78)的浓度及其与炎症细胞因子白介素6(IL-6)和单核细胞趋化蛋白-1(MCP-1)的关系。材料和方法：收集PDR和特发性黄斑裂孔(IMH)玻璃体切除患者的AQH和玻璃体标本。采用酶联免疫吸附试验(EL ISA)检测标本中ATF4、GRP78、IL-6、MCP-1的蛋白水平。结果：EL ISA分析显示，与对照组(均为P<；0.001)相比，PDR患者眼中AQH和玻璃体中ATF4和GRP78的水平均显著升高。PDR患者AQH和玻璃体标本中IL-6、MCP-1的平均浓度也高于IMH患者(均P<0.001)。(独立学生t检验、正态检验和偏度峰度检验)。此外，还分析了患者ATF4、GRP78与炎症因子IL-6、MCP-1的相关性。糖尿病视网膜病变患者眼组织中血管内皮生长因子4/IL-6和血管内皮生长因子4/单核细胞趋化蛋白-1浓度之间无显著相关性(r=0.346，p=0.072和r=0.275，p=0.157)。糖尿病视网膜病变患者血清GRP78/IL-6(r=0.724，p<；0.001)、GRP78/MCP-1(r=0.654，p<；0.001)均呈显著正相关。糖尿病视网膜病变患者玻璃体中ATF4/IL-6(r=0.918，p&t；0.001)、ATF4/MCP-1(r=0.921，p<；0.001)、GRP78/IL-6(r=0.978，p<；0.001)、GRP78/MCP-1(r=0.979，p<；0.001)呈显著正相关。IMH患者眼组织中ATF4/IL-6(r=0.187，p=474)、ATF4/MCP-1(r=0.240，p=0.353)、GRP78/IL-6(r=0.321，p=0.209)和GRP78/MCP-1(r=0.169，p=0.516)之间无显著相关性。玻璃体液中ATF4/IL-6(r=0.130，p=0.563)、ATF4/MCP-1(r=0.029，p=0.897)、GRP78/IL-6(r=0.078，p=0.717)、GRP78/MCP-1(r=0.005，p=0.982)之间无显著相关性。(皮尔逊相关系数(双尾))。结论：ATF4和GRP78可能在PDR的发病机制中起重要作用，并在病理过程中与炎性细胞因子IL-6和MCP-1协同作用。ATF4和GRP78可能是诊断PDR的良好生物标志物和新的治疗靶点。缩写：内质网应激；ATF4，激活转录因子4；GRP78，葡萄糖调节的78 kDa蛋白；AQH，房水；PDR，增殖性糖尿病视网膜病变；IL-6，IL-6；MCP-1，单核细胞趋化蛋白-1；IMH，特发性黄斑裂孔。
ABSTRACT Purpose: To determine concentrations of endoplasmic reticulum (ER) stress-related factors activating transcription factor 4 (ATF4) and glucose-regulated 78 kDa protein (GRP78) in vitreous and aqueous humor (AqH) of patients with proliferative diabetic retinopathy (PDR) and the correlation of ATF4, GRP78 and inflammatory cytokines interleukin-6(IL-6) and monocyte chemoattractant protein-1 (MCP-1). Materials and Methods: AqH and vitreous samples were collected from eyes of patients with PDR and idiopathic macular hole (IMH) which needed vitrectomy. Protein Levels of ATF4, GRP78, and IL-6, MCP-1 in samples were evaluated using enzyme-linked immunosorbent assay (ELISA). Results: ELISA analysis revealed significantly increased levels in both AqH and vitreous of ATF4 and GRP78 in eyes affected with PDR compared to the controls (all p < 0.001). The mean concentrations of IL-6, MCP-1 were also higher in both AqH and vitreous samples from patients with PDR compared to those of IMH (all p < 0.001). (Independent Student t-test, normality test followed with Skewness–Kurtosis Test). In addition, correlations of ATF4 and GRP78 with inflammatory factors IL-6 and MCP-1 in subjects of patients were analyzed. No significant correlation between the AqH concentrations of ATF4/IL-6 and ATF4/MCP-1 was detected in eyes of PDR patients (r = 0.346, p = 0.072 and r = 0.275, p = 0.157). Significant correlations were observed between AqH concentrations of GRP78/IL-6 (r = 0.724, p < 0.001), GRP78/MCP-1 (r = 0.654, p < 0.001) in PDR patients. Significant correlations were observed between vitreous concentrations of ATF4/IL-6 (r = 0.918, p < 0.001), ATF4/MCP-1 (r = 0.921, p < 0.001), GRP78/IL-6 (r = 0.978, p < 0.001), GRP78/MCP-1 (r = 0.979, p < 0.001) in PDR patients. No significant correlations was observed between AqH concentrations of ATF4/IL-6 (r = 0.187, p = 474), ATF4/MCP-1 (r = 0.240, p = 0.353), GRP78/IL-6 (r = 0.321, p = 0.209) and GRP78/MCP-1 (r = 0.169, p = 0.516) in eyes of IMH patients. And also no significant correlation was observed between vitreous concentrations of ATF4/IL-6 (r = 0.130, p = 0.563), ATF4/MCP-1(r = 0.029, p = 0.897), GRP78/IL-6 (r = 0.078, p = 0.717), GRP78/MCP-1 (r = 0.005, p = 0.982) in IMH patients. (Pearson correlation coefficient (two-tailed)). Conclusions: Our results demonstrated that ATF4 and GRP78 may play an important role in the pathogenesis of PDR and work in concert with inflammatory cytokines IL-6 and MCP-1 in pathological process. ATF4 and GRP78 may be good diagnostic biomarkers and new therapeutic targets for PDR. Abbreviations: ER stress, endoplasmic reticulum stress; ATF4, activating transcription factor 4; GRP78, glucose-regulated 78 kDa protein; AqH, aqueous humor; PDR, proliferative diabetic retinopathy; IL-6, interleukin-6; MCP-1, monocyte chemoattractant protein-1; IMH, idiopathic macular hole.