Department of Pharmacy, College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao, China.
Qingdao Eye Hospital of Shandong First Medical University, Qingdao, China; State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, Qingdao, China.
Exp Eye Res. 2021 Jan;202:108364. doi: 10.1016/j.exer.2020.108364. Epub 2020 Nov 20.
As a damage-associated molecular pattern molecule, high-mobility group box 1 protein (HMGB1) is involved in diabetes and its complications. However, the role of HMGB1 in diabetic keratopathy is not yet understood. The purpose of this study was to investigate the potential roles of HMGB1 in the development of diabetic keratopathy as well as potential strategies to block HMGB1 in order to prompt epithelial wound healing and nerve regeneration in diabetic corneas. The results demonstrated that diabetic keratopathy developed in mice over the duration of the diabetic condition with typical symptoms, including damaged ocular surfaces and corneal nerves. The diabetic corneas had significantly increased protein expression levels of HMGB1 and its receptors-the receptor for advanced glycation end products (RAGE) and toll-like receptor 4 (TLR4)-compared to the age-matched normal corneas (P < 0.05). Corneal HMGB1 levels significantly increased during the corneal wound healing process of the diabetic mice, peaking on the first day after the wound was created and then decreasing to the unwounded level on the seventh day. Exogenous HMGB1 peptide significantly retarded wound and nerve healing, while glycyrrhizin (an HMGB1 inhibitor) significantly prompted wound and nerve healing. Further, the western blot results confirmed that RAGE and TLR4 were also involved in corneal wound and nerve healing. In conclusion, these data showed that HMGB1 and its related receptors are highly involved in the development of diabetic keratopathy. This finding indicates that the blockage of HMGB1 might serve as a strategy to prompt diabetic corneal and nerve wound healing.
高迁移率族蛋白 B1（HMGB1）作为一种损伤相关分子模式分子，参与糖尿病及其并发症的发生。然而，HMGB1 在糖尿病性角膜病变中的作用尚不清楚。本研究旨在探讨 HMGB1 在糖尿病性角膜病变发展中的潜在作用，以及阻断 HMGB1 的潜在策略，以促进糖尿病角膜上皮伤口愈合和神经再生。结果表明，糖尿病小鼠在糖尿病状态下持续发展为糖尿病性角膜病变，表现出典型的症状，包括眼表和角膜神经损伤。与年龄匹配的正常角膜相比，糖尿病角膜的 HMGB1 及其受体（晚期糖基化终产物受体 [RAGE] 和 toll 样受体 4 [TLR4]）的蛋白表达水平显著增加（P<0.05）。在糖尿病小鼠角膜伤口愈合过程中，角膜 HMGB1 水平显著增加，在伤口形成后的第一天达到峰值，然后在第 7 天降至未受伤水平。外源性 HMGB1 肽显著延迟伤口和神经愈合，而甘草酸（HMGB1 抑制剂）则显著促进伤口和神经愈合。此外，Western blot 结果证实 RAGE 和 TLR4 也参与了角膜伤口和神经愈合。总之，这些数据表明 HMGB1 及其相关受体高度参与糖尿病性角膜病变的发生。这一发现表明，阻断 HMGB1 可能成为促进糖尿病性角膜和神经伤口愈合的一种策略。
