自噬与HMGB1在糖尿病视网膜微血管病变和神经退行性变中的研究进展

糖尿病视网膜病变（diabetic retinopathy,DR）是由糖尿病所导致的最典型的微血管并发症之一。以往DR发病机制和治疗的研究主要集中在微血管;近年来,许多学者认为DR不仅仅是一种微血管病变,而且还伴有视网膜神经退行性变。近期研究表明,自噬与高迁移率族蛋白B1（high mobility group box protein 1,HMGB1）通过多条通路参与到糖尿病视网膜微血管病变和神经退行性变中,通过调控自噬或 HMGB1可能为DR治疗提供一种新的思路。本文就自噬与 HMGB1 在糖尿病视网膜微血管病变和神经退行性变发病中的研究进展进行综述。     

从视网膜氧化应激与微血管改变谈糖尿病视网膜病变的发病机制和防治策略

糖尿病视网膜病变（DR）是糖尿病患者因长期高血糖而并发的视网膜微循环障碍性眼病，随病情进展可致严重视力损害。DR作为一种病因复杂的多因素疾病，尽管发病机制尚未完全阐明，但氧化应激已被证明是其中一个关键因素。高血糖引起机体多种代谢异常相互作用，诱导视网膜活性氧过度产生、氧化应激损伤增加，导致视网膜线粒体功能障碍、微血管功能障碍、血-视网膜屏障破坏、新生血管形成等一系列病理反应，显著影响DR发生发展的各个阶段。深入研究视网膜氧化应激与微血管改变在DR发病机制中的作用将有助于为防治DR提供新的思路。     

糖尿病视网膜病变微血管神经病变发病机制的研究进展

糖尿病视网膜病变(diabetic retinopathy,DR)是糖尿病(diabetic melitus,DM)常见且严重的微血管并发症之一。在国外,DR是工作人群(20～64岁)首位的致盲因素; 在国内,DR的发病率和致盲率也在逐年增加,严重影响患者的生存质量。以往对DR发病机制和治疗的研究主要集中在微血管方面,近年来,随着研究的深入,越来越多的学者认为DR不再单纯是一种微血管病变,同时伴随着视网膜神经退行性改变,但国内外文献对DR的微血管病变与神经退行性改变发病机制的研究多是单一的。本文就DR微血管病变与神经退行性改变之间的关系做一综述。     

db／db小鼠与糖尿病视网膜病变

糖尿病视网膜病变（DR）是糖尿病常见的微血管并发症之一,发病率逐年上升,对DR的发病机制及干预措施的研究日益受到重视。DR的发病机制主要包括葡萄糖毒性产物的形成及其对细胞信号通路的影响,导致血管性病变和神经性病变。研究表明,DR的发生可能与多元醇通路的活跃、氧化应激的增加、糖基化终末产物（AGEs）的形成、蛋白激酶C通路以及血管内皮生长因子（VEGF）表达的增强等相关。db／db小鼠作为一种自发性2型糖尿病动物模型,其发病机制与人类常见的2型糖尿病极为相似,在DR的研究中得到越来越广泛的应用。本文对db／db小鼠在DR中的研究进展进行综述,为进一步阐明DR的发病机制及制定有效的防治措施提供线索和思路。     

Mǖller细胞在糖尿病视网膜病变中的研究进展

糖尿病视网膜病变（diabetic retinopathy，DR）是糖尿病常见且严重的微血管并发症，近年来对DR发病机制的探讨已成为研究热点。Mǖller细胞是哺乳动物视网膜主要的神经胶质细胞，贯穿于整个视网膜，参与视网膜的许多病理和生理过程。随着对胶质细胞研究的深入，人们发现Mǖller细胞对DR的发病机制研究有着重要意义。     

星形胶质细胞与糖尿病视网膜病变

视网膜星形胶质细胞分布于神经元与毛细血管之间。在发育过程中，星形胶质细胞的成熟需要血管内皮细胞的诱导。视网膜星形胶质细胞参与血一视网膜屏障的形成，并对其功能进行调控；通过表达谷氨酸转运体参与谷氨酸代谢；通过产生的钙振荡对神经元细胞的活动进行调节；调节大分子物质在胶质细胞问的扩散。此外，星形胶质细胞还具有神经元营养保护功能。糖尿病视网膜病变（DR）发生时，视网膜星形胶质细胞的数量减少，其标志物GFAP的表达量减少、谷氨酸代谢能力减弱、COX-2表达、AR和VEGF表达量增加。由此可以推论：视网膜星形胶质细胞是神经元与血管细胞活动的桥梁。对星形胶质细胞的研究有助于揭示DR中神经元病变与血管病变之间的相互关系。     

M2型丙酮酸激酶在糖尿病视网膜病变中的作用

糖尿病视网膜病变(DR)是一种糖尿病中最常见的高度特异性微血管并发症,是全球20~65岁人群视力障碍和失明的主要原因,主要表现为视网膜内微血管的异常及新生血管的形成。糖酵解过程是从葡萄糖分解开始到丙酮酸生成的过程,可以为机体迅速提供能量,内皮细胞多数通过糖酵解产生的ATP来维持其功能,包括维持紧密连接和屏障作用。丙酮酸激酶(PK)的M2亚型(PKM2)作为糖酵解的关键酶,在机体的大多数组织中均有表达。内皮细胞和光感受器细胞作为视网膜中的重要细胞成分,在DR的发生发展过程中发挥重要作用。研究表明,PKM2通过代谢和非代谢方式调节内皮细胞和光感受器的功能,在DR发展中发挥重要作用。因此,本文将重点通过内皮细胞和光感受器细胞两个方面来综述PKM2在糖尿病视网膜病变中的研究进展,从而为DR的诊断和治疗提供新思路。     

蛋白质组学应用于糖尿病视网膜病变发病机制的研究进展

糖尿病视网膜病变(DR)是糖尿病的一种微血管并发症,是导致失明的主要疾病之一。过去常认为DR的发生及进展与糖尿病的病程长、血糖控制不佳及高血脂有关。然而,许多糖尿病患者不伴有这些危险因素仍然发生DR,甚至一些病程长的糖尿病患者没有发生DR。事实上,DR的病理变化是涉及微血管病变、神经退化、免疫及继发性炎症反应等多种因素相互作用的结果。生物标志物能客观地预示疾病的发生,监控疾病的进展,评估治疗的疗效。研究DR发病的分子机制能有助于找到特异性的生物标志物以及新的治疗靶点。蛋白质组学是通过高通量、快速鉴定与定量分析细胞、组织、体液中所有蛋白质的组成、功能及蛋白之间的相互作用的学科。该文就最新的蛋白质组学研究技术,以及近几年运用该技术发现的DR生物分子标志物进行一综述。     

补体功能失调对糖尿病视网膜病变的影响

糖尿病视网膜病变(DR)是糖尿病常见的神经和微血管并发症之一,也是20~74岁人群发生视力障碍的主要原因之一。DR的发病机制至今仍未完全阐明,近年来补体功能失调在DR中的作用受到关注。补体因子及补体调节蛋白异常影响视网膜血管周细胞、内皮细胞、神经细胞及胶质细胞的命运和功能,因而可能作为DR治疗的新靶点。就眼内补体的特点,DR与补体功能失调关系的研究进展,DR中补体基因的多态性和靶向补体分子的探索性治疗成果进行综述,为开展相关研究提供新的思路。     

糖尿病视网膜病变细胞生物学研究进展

糖尿病视网膜病变（DR）是主要的致盲眼病。几十年来，内分泌学家和眼科学家一直认为，视网膜血管内皮细胞和周细胞在糖尿病视网膜病理改变中发挥了主导作用，而神经元和胶质细胞处于从属的地位。最新研究显示，DR除了微血管病理改变外，还是一种神经组织的慢性退行性变。在DR过程中，神经元和神经胶质细胞不仅能和血管内皮细胞、周细胞发生信息交流，而且神经元、胶质细胞彼此之间也能发生信息交流。根据这些已经取得的进展，神经视网膜可能在DR的形成以及病变的修复中担负着至关重要的作用。从细胞生物学的角度对这一领域的研究进展作一综述。     

糖尿病视网膜病变中视网膜内皮细胞功能障碍的研究进展

视网膜内皮细胞(REC)是参与糖尿病视网膜病变和许多眼部疾病的主要细胞类型之一。视网膜微血管系统有助于血-视网膜屏障的维持,这对正常的视功能至关重要。REC的改变在视网膜疾病的发生发展中起着关键作用。高血糖是糖尿病微血管损伤的重要原因,通过不同的机制导致REC功能障碍,包括向衰老表型改变、迁移和增殖能力增强、炎性凋亡等,最终导致无细胞毛细血管及病理性新生血管形成。本文对糖尿病视网膜病变中REC的功能障碍作一综述。     

Dyslipidemia, but not hyperglycemia, induces inflammatory adhesion molecules in human retinal vascular endothelial cells

PURPOSE: The initial determinants of retinal microvascular damage in diabetic retinopathy are not well understood, but are likely to be induced by hyperglycemia and/or dyslipidemia. The purpose of this study was to examine the effect of fatty acids and hyperglycemia on human retinal vascular endothelial (hRVE) cells as a means of mimicking diabetic metabolic disorders. METHODS: The expression of adhesion molecules in hRVE and human umbilical vein endothelial cells (HUVECs) was assayed by Western blot analysis and confirmed by leukocyte adhesion assay. The mechanisms underlying the induction of adhesion molecules by fatty acids were further investigated by using cyclooxygenase (COX), lipoxygenase (LOX), and P450 monooxygenase (MOX) inhibitors. RESULTS: Treatment of hRVE cells with the n6 polyunsaturated fatty acids (PUFAs) 18:2n6 and 20:4n6 for up to 24 hours resulted in a significant induction of intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 protein levels. In contrast, treatment with high glucose (22 mM) for 24 hours did not affect CAM expression. Induction of CAM by n6 PUFA correlated with enhanced leukocyte binding to hRVE cells. The effect of n6 PUFA on ICAM-1 and VCAM-1 was blocked by an inhibitor of LOX, but not by COX or MOX inhibitors. In contrast to hRVE cells, n6 PUFA did not induce ICAM-1 or VCAM-1 in HUVECs. CONCLUSIONS: The data obtained in this study demonstrate that acute exposure to linoleic or arachidonic acid, but not hyperglycemia, induces inflammatory adhesion molecule expression in the presence of LOX in microvascular hRVE cells, but not in HUVECs. These results are consistent with the emerging hypothesis recognizing early-stage diabetic retinopathy as a low-grade chronic inflammatory disease.     

Mechanism of diabetes-induced microvascular damage and therapeutic potential of ROCK inhibition

The rapid increase in diabetic retinopathy (DR), a common ocular complication of diabetes mellitus, necessitates the development of new therapeutic strategies for the amelioration and treatment of DR, especially in the earlier stages. In the present study, involvement of the Rho/Rho-kinase (ROCK) pathway in diabetic microvasculopathy and the therapeutic potential of fasudil, a selective ROCK inhibitor, were investigated. Retinal microvascular damage secondary to increased leukocyte adhesion substantially contributes to DR in its early stages. Significant Rho/ ROCK activation was observed in the retinal microvasculature of diabetic rats. The ROCK inhibitor, fasudil, protects the vascular endothelium by inhibit- ing leukocyte adhesion and reducing leukocyte-induced endothelial injury mediated through the restoration of endothelial nitric oxide synthase activity, in the retinas of diabetic rats. In co-culture assay of DR leukocytes and microvascular endothelial cells, we investigated the protective mechanisms of fasudil on endothelial damage using L-NAME, an inhibitor of nitric oxide synthase. Leukocytes from DR patients caused endothelial apoptosis via Fas/ FasL interaction, which was significantly reduced by a ROCK inhibition dependent on nitric oxide. The Rho/ROCK pathway plays a critical role in diabetic retinal microvasculopathy and ROCK inhibition may become a new strategy in the amelioration and treatment of DR, especially in its early stages.     

Human diabetic serum does not stimulate bovine retinal endothelial cell growth in culture

Bovine retinal microvascular endothelial cells were cultured with serum from nondiabetic controls, patients with background, preproliferative, proliferative and inactive (treated) proliferative diabetic retinopathy. Using Coomassie Blue to measure cellular protein, we found no significant increase in retinal endothelial cell growth with serum from patients with preproliferative or proliferative retinopathy.     

Pathogenetic potential of leukocytes in diabetic retinopathy

Recently, increasing interest has been directed toward the role of leukocytes in microvascular disorders including diabetic retinopathy because of their large cell volume, high cytoplasmic rigidity, natural tendency to stick to the vascular endothelium, and capacity to generate toxic superoxide radicals and proteolytic enzymes. Leukocytes in diabetes are reported to be less deformable and more activated, and may be involved in capillary non-perfusion, endothelial cell damage, and vascular leakage in the retinal microcirculation. In fact, histological studies show many capillary occlusions by leukocytes and capillary dropout or degeneration associated with leukocytes in the diabetic retina. Serial acridine orange leukocyte fluorography and fluorescein angiography studies also identify trapped leukocytes directly associated with areas of downstream non-perfusion in the diabetic retinal microcirculation. More recent studies suggest that adhesion molecules may mediate retinal leukocyte stasis (leukostasis) in diabetes and a reduction in the leukostasis by anti-adhesion antibodies can suppress retinal vascular leakage. In addition, some agents inhibiting leukostasis are reported to improve retinal abnormalities induced by diabetes. Thus, leukostasis in the retinal microcirculation can be a new promising target in the treatment of diabetic retinopathy.     

Hyperhomocysteinemia in patients with diabetes mellitus with and without diabetic retinopathy

OBJECTIVE: To evaluate the prevalence of hyperhomocysteinaemia in diabetic patients with no diabetic retinopathy (no DR), with non-proliferative diabetic retinopathy (NPDR) and with proliferative diabetic retinopathy (PDR). RESEARCH DESIGN AND METHODS: This prospective, case-control study, included 179 diabetic patients and 156 age-matched controls with no diabetes and no history of ocular disease, who were undergoing routine physical checkups. Plasma homocysteine levels of all study participants were measured using high-performance liquid chromatography (HPLC). Hyperhomocysteinaemia was defined when homocysteine levels were higher than 15 micromol/l. RESULTS: The mean plasma homocysteine level was 11.75+-0.24 in the control group,13.46+0.74 in the no DR group, 14.56 + 0.64 in the NPDR group and 15.86 + 1.34 in the PDR group. Mean homocysteine levels were significantly elevated in the NPDR and PDR groups compared to the control group(P = 0.001 and <0.0001, respectively). The prevalence of hyperhomocysteinaemia was also higher in the NPDR and PDR groups compared to the control group (P = 0.032 and 0.011, respectively). No statistically significant difference was found between the no DR and the control group. CONCLUSIONS: Our findings suggest that hyperhomocysteinaemia may be associated with diabetic retinopathy and partially explain the increased risk of microvascular angiopathy occurring in these patients.     

细胞因子与糖尿病视网膜病变的研究进展

糖尿病视网膜病变（DR）是一种发生进行性视力损害的糖尿病（DM）并发症,其特征是毛细血管闭锁、微循环障碍和局部缺血性视网膜新生血管形成,其确切的发病机制尚不清楚。最近有研究认为DR可能与视网膜毛细血管炎症反应有关。由于细胞因子能引起炎症反应和黏附分子表达,因此细胞因子增加单核细胞和内皮细胞黏附的过程被认为是DR发生发展过程中的关键事件。就血管内皮生长因子（VEGF）、转化生长因子-β（TGF-β）、碱性成纤维细胞生长因子（bFGF）等多种细胞因子在DR中的作用进行综述。     

Diabetic retinopathy. Pathophysiology and therapy of hypoxia-induced inflammation

Diabetic retinopathy is the most common chronic microvascular complication associated with diabetes mellitus. The development of diabetic retinopathy is a consequence of metabolic dysregulation. Hyperglycemia is a critical factor which is involved in basement membrane thickening, loss of pericytes and endothelial cells, and retinal capillary nonperfusion. We review the molecular basis of diabetic retinopathy and maculopathy and elaborate the role of growth factors and cytokines in the development of diabetic vascular alterations, their specific influence on the cellular interaction between retinal endothelial cells and pericytes, and the role of intravascular blood components.     

Ⅱ型糖尿病性视网膜病变患者角膜内皮细胞结构变化的研究

目的：探讨非胰岛素依赖型糖尿病合并视网膜病变后其内皮细胞密度及形态学的变化。方法：选择40例糖尿病视网膜病变患者，分为增殖型视网膜病变组和非增殖型视网膜病变组。观察其内皮细胞密度及形态学变化，并与正常对照组进行比较，统计学分析。结果：糖尿病增殖型视网膜病变患者角膜内皮细胞密度及六边形细胞百分比明显降低，变异系数增加，糖尿病非增殖型视网膜病变患者角膜内皮细胞密度降低，形态学与下对照组比较差异无显著性。结论：非胰岛素依赖型糖尿病视网膜病变患者其角膜内皮细胞结构有异常变化。     

Hydrogen Sulfide: A Potential Therapeutic Target in the Development of Diabetic Retinopathy

PurposeHyperglycemia damages the retinal mitochondria, and the mitochondrial damage plays a central role in the development of diabetic retinopathy. Patients with diabetes also have higher homocysteine levels, and abnormalities in homocysteine metabolism result in decreased levels of hydrogen sulfide (H₂S), an endogenous gasotransmitter signaling molecule with antioxidant properties. This study aimed to investigate the role of H₂S in the development of diabetic retinopathy.MethodsStreptozotocin-induced diabetic mice were administered a slow releasing H₂S donor GYY4137 for 6 months. The retina was used to measure H₂S levels, and their retinal vasculature was analyzed for the histopathology characteristic of diabetic retinopathy and oxidative stress, mitochondrial damaging matrix metalloproteinase-9 (MMP-9), and mitochondrial integrity. These parameters were also measured in the isolated retinal endothelial cells incubated in high glucose medium containing GYY4137.ResultsAdministration of GYY4137 to diabetic mice ameliorated decrease in H₂S and prevented the development of histopathology, characteristic of diabetic retinopathy. Diabetes-induced increase in oxidative stress, MMP-9 activation, and mitochondrial damage were also attenuated in mice receiving GYY4137. Results from isolated retinal endothelial cells confirmed the results obtained from diabetic mice.ConclusionsThus, supplementation of H₂S donor prevents the development of diabetic retinopathy by ameliorating increase in oxidative stress and preserving the mitochondrial integrity. H₂S donors may provide a novel therapeutic strategy to inhibit the development of diabetic retinopathy.