Exendin-4 alleviates retinal vascular leakage by protecting the blood-retinal barrier and reducing retinal vascular permeability in diabetic Goto-Kakizaki rats
Exendin-4 alleviates retinal vascular leakage by protecting the blood-retinal barrier and reducing retinal vascular permeability in diabetic Goto-Kakizaki rats
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DOI：
10.1016/j.exer.2014.05.004
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发表时间：
2014-10-01
影响因子：
3.4
通讯作者：
Zhang, Yu
中科院分区：
文献类型：
--
作者：
Fan, Yichao;Liu, Kun;Zhang, Yu
内皮血视网膜屏障（BRB）的破坏和随后的视网膜血管渗漏是糖尿病视网膜病变（DR）导致视力丧失的主要原因。 Exendin-4 (E4) 是一种胰高血糖素样肽 1 激素受体 (GLP-1R) 的长效激动剂，广泛应用于临床，并显示出神经保护作用。我们之前的研究证明了E4在早期实验性DR中的保护作用；然而，介导这种保护作用的分子和细胞机制尚不完全清楚。 BRB 在 DR 中发挥着关键作用。我们推测E4可能对BRB发挥保护作用。为了检验这一假设，将E4（0.1μg/2μL/眼）或媒介物玻璃体内注射到糖尿病Goto-Kakizaki（GK）大鼠和对照动物中。结果显示，E4 显着抑制 GK 大鼠视网膜电图 (ERG) 振幅的降低，特别是 b 波和振荡电位 (OP)。 E4 通过 ERK 和 AKT/PKB 途径上调视网膜 GLP-1R 表达并下调胎盘生长因子 (PLGF) 和血管内皮生长因子 (VEGF) 表达。 E4 抑制紧密连接蛋白（即claudin-5 和occludin）表达的减少和伊文思蓝渗透（EBP）的增加。在体外高葡萄糖浓度培养的原代大鼠 Muller 细胞中也发现了类似的结果。我们得出结论，E4 可以通过减少 PLGF 和 ICAM-1 表达并维持 BRB 的完整性来保护 BRB 免受糖尿病损伤。因此，E4治疗可能是治疗DR的有效方法。 (C) 2014 Elsevier Ltd. 保留所有权利。
The breakdown of the inner endothelial blood-retinal barrier (BRB) and subsequent retinal vascular leakage are the main causes of vision loss due to diabetic retinopathy (DR). Exendin-4 (E4) is a long-acting agonist of the glucagon-like peptide 1 hormone receptor (GLP-1R) that is widely used in clinics and has shown a neuroprotective effect. Our previous studies demonstrated the protective effect of E4 in early experimental DR; however, the molecular and cellular mechanisms that mediate this protective effect are not fully known. The BRB plays a key role in DR. We speculated that E4 may exert its protective effects on the BRB. To test this hypothesis, E4 (0.1 mu g/2 mu L/eye) or vehicle were intravitreally injected into diabetic Goto-Kakizaki(GK) rats and control animals. The results revealed that E4 significantly inhibited the reductions in electroretinogram (ERG) amplitudes in the GK rats, particularly in the b-wave and oscillatory potentials (OPs). E4 upregulated retinal GLP-1R expression and downregulated the expressions of placental growth factor (PLGF) and vascular endothelial growth factor (VEGF) via the ERK and AKT/PKB pathways. Decreases in tight junction protein (i.e., claudin-5 and occludin) expression and increases in Evans blue permeation (EBP) were inhibited by E4. Similar results were also found in primary rat Muller cells in high glucose concentration cultures in vitro. We conclude that E4 may protect the BRB from diabetic insults by decreasing PLGF and ICAM-1 expression and maintaining the integrity of the BRB. Thus, E4 treatment may be an effective therapeutic approach for DR. (C) 2014 Elsevier Ltd. All rights reserved.