Inhibition of HMGB1 as a protective mechanism against diabetic retinopathy

糖尿病视网膜病变仍然是工作年龄成年人视力丧失的主要原因。以前的研究 导致了抗血管内皮生长因子疗法的发展，这是一种有效的增生性疾病的治疗方法 一些患者出现糖尿病视网膜病变和黄斑水肿，而另一些患者则无反应。为 治疗非增殖性糖尿病视网膜病变，除了良好的血糖控制外，几乎没有可用的选择， 这对许多患者来说是个问题。最近的发现为我们提供了对分子的新见解 糖尿病视网膜病变的机制表明，除了氧化应激外， 炎症可能是糖尿病视网膜损伤的主要致病因素。我们最近报道了 高糖显著增加高迁移率族蛋白1(HMGB1)的蛋白水平，表明 警报系统在调节视网膜对高糖反应中的潜在作用。HMGB1是 广泛参与炎症；它可以作为伴侣调节细胞核内的转录， 由免疫细胞分泌，与P53相互作用，激活细胞因子释放。因此，它提供了一个 抑制视网膜炎症反应的前景看好的靶点。由于它的多种机制， 不同细胞类型的激活和作用，提高对HMGB1细胞调控的理解 视网膜的活动变得越来越重要。我们的初步数据表明，类胰岛素 生长因子结合蛋白3(IGFBP-3)可抑制高糖诱导的HMGB1水平升高 在视网膜内皮细胞(REC)。我们之前已经报道过IGFBP-3 KO小鼠有视网膜 尽管血糖水平正常，但损害类似于糖尿病视网膜病变的啮齿动物模型。除了……之外 IGFBP-3，研究表明PKA可以直接磷酸化酵母HMGB1的A盒区域 导致HMGB1活性降低。研究还表明，增加的SIRT1促进了脱乙酰基 HMGB1，导致细胞质易位减少。因此，调查是有科学依据的。 PKA、Epac1、IGFBP-3和SIRT1对HMGB1的调节。此外，对HMGB1的抑制作用 使用抑制剂(甘草酸)的活动恢复了视网膜厚度并减少了视网膜退行性变 小鼠视网膜缺血/再灌注损伤体内模型中的毛细血管。这些数据导致了 假设抑制视网膜中的HMGB1活性可以预防糖尿病引起的损伤。我们的 总体目标是确定PKA和Epac1通路抑制的机制 HMGB1/炎症诱导的视网膜损伤，并作为可能阻止糖尿病的保护途径 视网膜受损。

Diabetic retinopathy remains the leading cause of vision loss in working age adults. Previous research has led to the development of anti-VEGF therapy, which is an effective treatment for proliferative diabetic retinopathy and macular edema in some patients, while other patients are unresponsive. For treatment of non-proliferative diabetic retinopathy, few options are available save good glycemic control, which is problematic for many patients. Recent discoveries offer new insights into the molecular mechanisms underlying diabetic retinopathy and suggest that in addition to oxidative stress, increased inflammation may be a major causative factor in diabetes-induced retinal damage. We recently reported that high glucose significantly increased high mobility group box 1 (HMGB1) protein levels, suggesting a potential role for the alarmin system in regulating retinal responses to high glucose. HMGB1 is extensively involved in inflammation; it can serve as a chaperone to regulate transcription in the nucleus, is secreted by immune cells, interacts with p53, and activates cytokine release. As such, it provides a promising target to blunt the inflammatory response in the retina. Due to its multiple mechanisms of activation and roles in various cell types, an improved understanding of the cellular regulation of HMGB1 actions in the retina becomes increasingly important. Our preliminary data demonstrate that insulin-like growth factor binding protein 3 (IGFBP-3) can inhibit high glucose-induced increases in HMGB1 levels in retinal endothelial cells (REC). We have previously reported that IGFBP-3 KO mice have retinal damage similar to rodent models of diabetic retinopathy, despite normal glucose levels. In addition to IGFBP-3, studies have shown that PKA can directly phosphorylate the Box A region of yeast HMGB1 leading to decreased HMGB1 actions. Studies also showed that increased SIRT1 promoted deacetylation of HMGB1, leading to reduced cytoplasmic translocation. Thus, there is scientific rationale to investigate the regulation of HMGB1 by PKA, Epac1, IGFBP-3, and SIRT1. Furthermore, inhibition of HMGB1 activity using an inhibitor (glycyrrhizin) restored retinal thickness and reduced retinal degenerate capillaries in an in vivo model of retinal ischemia/reperfusion injury in mice. These data have led to the hypothesis that inhibition of HMGB1 activity in the retina protects against diabetes-induced damage. Our overall goal is to determine the mechanisms by which the PKA and Epac1 pathways inhibit HMGB1/inflammation-induced retinal injury and serve as protective pathways that may block diabetic retinal damage.