色素上皮衍生因子（PEDF）在实验性糖尿病性视网膜病变早期的保护作用。

Protective role of pigment epithelium-derived factor (PEDF) in early phase of experimental diabetic retinopathy.

机构信息

Department of Ophthalmology, Kurume University School of Medicine, Kurume, Japan.

出版信息

Diabetes Metab Res Rev. 2009 Oct;25(7):678-86. doi: 10.1002/dmrr.1007.

DOI:10.1002/dmrr.1007

PMID:19685553

Abstract

BACKGROUND

Pigment epithelium-derived factor (PEDF) is the most potent inhibitor of angiogenesis in the mammalian eye, thus suggesting that PEDF may protect against proliferative diabetic retinopathy. However, a role for PEDF in early diabetic retinopathy remains to be elucidated. We investigated here whether and how PEDF could prevent the development of diabetic retinopathy.

METHODS

Streptozotocin-induced diabetic rats were treated with or without intravenous injection of PEDF for 4 weeks. Early neuronal derangements were evaluated by electroretinogram (ERG) and immunofluorescent staining of glial fibrillary acidic protein (GFAP). Expression of PEDF and 8-hydroxydeoxyguanosine (8-OHdG), a marker of oxidative stress, was localized by immunofluorescence. Vascular endothelial growth factor (VEGF) and p22phox expression were evaluated with western blots. Breakdown of blood retinal barrier (BRB) was quantified with fluorescein isothiocynate (FITC)-conjugated dextran. NADPH oxidase activity was measured with lucigenin luminescence.

RESULTS

Retinal PEDF levels were reduced, and amplitudes of a- and b-wave in the ERG were decreased in diabetic rats, which were in parallel with GFAP overexpression in the Müller cells. Further, retinal 8-OHdG, p22phox and VEGF levels and NADPH oxidase activity were increased, and BRB was broken in diabetic rats. Administration of PEDF ameliorated all of the characteristic changes in early diabetic retinopathy.

CONCLUSIONS

Results suggest that PEDF could prevent neuronal derangements and vascular hyperpermeability in early diabetic retinopathy via inhibition of NADPH oxidase-driven oxidative stress generation. Substitution of PEDF may offer a promising strategy for halting the development of diabetic retinopathy.

摘要

背景

色素上皮衍生因子（PEDF）是哺乳动物眼中最有效的血管生成抑制剂，因此提示 PEDF 可能对增生性糖尿病视网膜病变有保护作用。然而，PEDF 在早期糖尿病视网膜病变中的作用仍有待阐明。我们在此研究了 PEDF 是否以及如何预防糖尿病视网膜病变的发展。

方法

链脲佐菌素诱导的糖尿病大鼠接受或不接受 PEDF 静脉注射治疗 4 周。通过视网膜电图（ERG）和神经胶质纤维酸性蛋白（GFAP）的免疫荧光染色评估早期神经元紊乱。通过免疫荧光定位 PEDF 和 8-羟基脱氧鸟苷（8-OHdG）的表达，8-OHdG 是氧化应激的标志物。用 Western blot 评估血管内皮生长因子（VEGF）和 p22phox 的表达。用异硫氰酸荧光素（FITC）-结合葡聚糖定量血视网膜屏障（BRB）的破坏。用荧光素发光测量 NADPH 氧化酶活性。

结果

视网膜 PEDF 水平降低，糖尿病大鼠 ERG 的 a-和 b-波幅度降低，与 Müller 细胞中 GFAP 的过度表达平行。此外，视网膜 8-OHdG、p22phox 和 VEGF 水平以及 NADPH 氧化酶活性升高，BRB 在糖尿病大鼠中破坏。PEDF 的给药改善了早期糖尿病视网膜病变的所有特征性变化。