使用晚期糖基化终产物受体的可溶性形式抑制糖尿病性白细胞淤滞和血视网膜屏障破坏。

Inhibition of diabetic leukostasis and blood-retinal barrier breakdown with a soluble form of a receptor for advanced glycation end products.

作者信息

Kaji Yuichi, Usui Tomohiko, Ishida Susumu, Yamashiro Kenji, Moore Tara C B, Moore Jonathan, Yamamoto Yasuhiko, Yamamoto Hiroshi, Adamis Anthony P

机构信息

Department of Ophthalmology, University of Tsukuba, Institute of Clinical Medicine, Ibaraki, Japan.

出版信息

Invest Ophthalmol Vis Sci. 2007 Feb;48(2):858-65. doi: 10.1167/iovs.06-0495.

DOI:10.1167/iovs.06-0495

PMID:17251488

Abstract

PURPOSE

The interaction of advanced glycation end products (AGEs) with their receptors is hypothesized to be involved in the development of diabetic retinopathy. In the present study, the role of an AGE receptor, RAGE, was investigated in the development of diabetic retinopathy in vivo.

METHODS

C57/BJ6 and RAGE-transgenic mice that carried human RAGE genetic DNA under the control of the murine flk-1 promoter were made diabetic with streptozocin. Three months after the onset of diabetes, the soluble form of RAGE (sRAGE) or mouse serum albumin was injected intraperitoneally at 100 mug/d for 14 consecutive days. After the final injection, blood-retinal barrier breakdown, retinal leukostasis, expression of VEGF and ICAM-1, and expression of RAGE in the retina were investigated.

RESULTS

Blood-retinal barrier breakdown and increased leukostasis were associated with the experimental diabetes in the C57/BJ6 mice. These changes were significantly augmented in RAGE-transgenic mice. The blood-retinal barrier breakdown and leukostasis in the diabetic C57/BJ6 and RAGE-transgenic mice were accompanied by increased expression of VEGF and ICAM-1 in the retina. The systemic administration of sRAGE significantly inhibited blood-retinal barrier breakdown, leukostasis, and expression of ICAM-1 in the retina in both the diabetic C57/BJ6 and RAGE-transgenic mice. The expression of RAGE was slightly increased in the retinal vessels in diabetic or RAGE-transgenic mice. Furthermore, a strong induction of RAGE was observed in the retinal vessels of diabetic RAGE-transgenic mice.

CONCLUSIONS

This study further demonstrates the role of the AGEs and RAGE axis in blood-retinal barrier breakdown and the retinal leukostasis, which are characteristic clinical symptoms of diabetic retinopathy. Furthermore, these data demonstrate that blocking AGE bioactivity may be effective for the treatment of diabetic retinopathy.

摘要

目的

据推测，晚期糖基化终末产物（AGEs）与其受体的相互作用参与了糖尿病视网膜病变的发展。在本研究中，研究了AGE受体RAGE在糖尿病视网膜病变体内发展过程中的作用。

方法

将C57/BJ6小鼠和携带在小鼠flk-1启动子控制下的人类RAGE基因DNA的RAGE转基因小鼠用链脲佐菌素诱导成糖尿病。糖尿病发病三个月后，连续14天每天腹腔注射100μg可溶性RAGE（sRAGE）或小鼠血清白蛋白。最后一次注射后，研究血视网膜屏障破坏、视网膜白细胞停滞、VEGF和ICAM-1的表达以及视网膜中RAGE的表达。

结果

C57/BJ6小鼠的血视网膜屏障破坏和白细胞停滞增加与实验性糖尿病有关。这些变化在RAGE转基因小鼠中显著加剧。糖尿病C57/BJ6小鼠和RAGE转基因小鼠的血视网膜屏障破坏和白细胞停滞伴随着视网膜中VEGF和ICAM-1表达的增加。全身性给予sRAGE显著抑制了糖尿病C57/BJ6小鼠和RAGE转基因小鼠的血视网膜屏障破坏、白细胞停滞以及视网膜中ICAM-1的表达。糖尿病或RAGE转基因小鼠视网膜血管中RAGE的表达略有增加。此外，在糖尿病RAGE转基因小鼠的视网膜血管中观察到RAGE的强烈诱导。