Fan Yichao, Liu Kun, Wang Qingping, Ruan Yuanyuan, Ye Wen, Zhang Yu
Department of Ophthalmology, Huashan Hospital Affiliated to Fudan University, 12 Middle Wulumuqi Road, Shanghai, China.
Department of Ophthalmology, First People's Hospital of Shanghai Affiliated with Shanghai Jiaotong University, Shanghai, China.
Exp Eye Res. 2014 Oct;127:104-16. doi: 10.1016/j.exer.2014.05.004. Epub 2014 Jun 6.
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 μg/2 μL/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 Müller 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.
视网膜内皮层血视网膜屏障（BRB）的破坏及随后的视网膜血管渗漏是糖尿病性视网膜病变（DR）导致视力丧失的主要原因。艾塞那肽-4（E4）是胰高血糖素样肽1激素受体（GLP-1R）的长效激动剂，在临床上广泛应用并已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中起关键作用。我们推测E4可能对BRB发挥保护作用。为验证这一假设，将E4（0.1μg/2μL/眼）或赋形剂玻璃体内注射到糖尿病Goto-Kakizaki（GK）大鼠和对照动物体内。结果显示，E4显著抑制了GK大鼠视网膜电图（ERG）振幅的降低，尤其是b波和振荡电位（OPs）。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）的表达。E4抑制了紧密连接蛋白（即claudin-5和occludin）表达的降低以及伊文思蓝渗透（EBP）的增加。在体外高糖浓度培养的原代大鼠Müller细胞中也发现了类似结果。我们得出结论，E4可能通过降低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DR的一种有效治疗方法。
