Department of Ophthalmology, Huashan Hospital, Fudan University, Shanghai, China.
Invest Ophthalmol Vis Sci. 2011 Jan 5;52(1):278-85. doi: 10.1167/iovs.09-4727.
To evaluate the protective effect of intravitreal injection of exendin-4 analogue (E4a) in early diabetic retinopathy (DR) and to explore its possible mechanism.
Forty Sprague-Dawley rats were divided into three groups: normal (N), diabetic (D), and E4a-treated diabetic rats (E4a). Diabetes was induced by streptozotocin. Rats in the E4a group were treated with E4a (0.1 μg/2μL/eye), whereas the N and D groups were treated with the equivalent volume of normal saline. Electroretinography was performed at 1 month and 3 months after diabetes onset. Thicknesses and cell counts in each layer of the retina were evaluated. The concentration of glutamate was measured by high-performance liquid chromatography (HPLC). Expressions of glucagon-like peptide-1 receptor (GLP-1R) and GLAST (excitatory amino acid transporter) were detected at mRNA and protein levels and verified by immunohistochemistry in vitro and in vivo. The rMc-1 cells were cultured under high-glucose medium (25 mM), which mimicked diabetic conditions. Effects of E4a (10 μg/mL) were also tested in the rMc-1 culture system.
E4a prevented the reduction in b-wave amplitude and oscillatory potential amplitude caused by diabetes. It also prevented the cell loss of outer nuclear layer and inner nuclear layer; the thickness and cell count in the outer nuclear layer were decreased in 1-month diabetic rats. The concentration of glutamate in the retina was higher in diabetic rats and was significantly reduced in the E4a-treated group. Consistent with such changes, retinal GLP-1R and GLAST expression were reduced in the diabetic retina but upregulated in E4a-treated rats. No improvement was found in the retina in both functional and morphologic parameters 3 months after treatment.
Intravitreal administration of E4a can prevent the retina, functionally and morphologically, from the insults of diabetes in rats. GLP-1R and GLAST were proved to exist in the rat retina, and their lowered expressions in the diabetic retina might be related to retinal damage by increasing the retinal glutamate. E4a might protect the retina by reducing the glutamate level through upregulating GLP-1R and GLAST, as observed in retinal Müller cells in this study, but this protective effect was transient. Thus, this could be a potential approach for the treatment of DR.
评价玻璃体内注射 exendin-4 类似物（E4a）对早期糖尿病视网膜病变（DR）的保护作用，并探讨其可能的机制。
40 只 Sprague-Dawley 大鼠分为三组：正常（N）组、糖尿病（D）组和 E4a 治疗糖尿病组（E4a）。糖尿病通过链脲佐菌素诱导。E4a 组大鼠给予 E4a（0.1 μg/2μL/眼）治疗，N 组和 D 组大鼠给予等体积生理盐水治疗。糖尿病发病后 1 个月和 3 个月行视网膜电图检查。评估视网膜各层厚度和细胞计数。高效液相色谱法（HPLC）测定谷氨酸浓度。体外和体内通过免疫组化法检测胰高血糖素样肽-1 受体（GLP-1R）和谷氨酸转运体（GLAST）的表达，并验证其mRNA 和蛋白水平。将 rMc-1 细胞在高糖培养基（25 mM）中培养，模拟糖尿病状态。还在 rMc-1 培养系统中测试了 E4a（10 μg/mL）的作用。
E4a 可防止糖尿病引起的 b 波振幅和振荡电位振幅降低。它还可防止外核层和内核层细胞丢失；1 个月糖尿病大鼠外核层厚度和细胞计数减少。糖尿病大鼠视网膜谷氨酸浓度升高，E4a 治疗组明显降低。与这些变化一致，糖尿病视网膜中 GLP-1R 和 GLAST 表达降低，但在 E4a 治疗大鼠中上调。治疗 3 个月后，视网膜在功能和形态参数方面均无改善。
玻璃体内给予 E4a 可在大鼠体内从功能和形态上预防视网膜受到糖尿病的损害。GLP-1R 和 GLAST 存在于大鼠视网膜中，其在糖尿病视网膜中的低表达可能与通过增加视网膜谷氨酸导致的视网膜损伤有关。E4a 可能通过上调 GLP-1R 和 GLAST 降低谷氨酸水平来保护视网膜，正如本研究中观察到的视网膜 Müller 细胞一样，但这种保护作用是短暂的。因此，这可能是治疗 DR 的一种潜在方法。
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