Inhibition of diabetic leukostasis and blood-retinal barrier breakdown with a soluble form of a receptor for advanced glycation end products
Inhibition of diabetic leukostasis and blood-retinal barrier breakdown with a soluble form of a receptor for advanced glycation end products
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DOI：
10.1167/iovs.06-0495
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发表时间：
2007-02-01
影响因子：
4.4
通讯作者：
Adamis, Anthony P.
中科院分区：
文献类型：
--
作者：
Kaji, Yuichi;Usui, Tomohiko;Adamis, Anthony P.
目的.晚期糖基化终末产物（AGEs）与其受体的相互作用被推测参与了糖尿病视网膜病变的发展。在本研究中，年龄受体，β-内酰胺酶，在体内糖尿病视网膜病变的发展中的作用进行了调查。C57/BJ 6和RAGE转基因小鼠携带人类基因组DNA，受鼠flk-1启动子控制，用链脲佐菌素使其患糖尿病。糖尿病发作后3个月，连续14天腹膜内注射可溶性形式的β-淀粉样蛋白（β-淀粉样蛋白）或小鼠血清白蛋白，剂量为100 μ g/d。在最后一次注射后，研究视网膜中的血-视网膜屏障破坏、视网膜白细胞停滞、VEGF和ICAM-1的表达以及VEGF的表达。血-视网膜屏障破坏和白细胞淤滞增加与C57/BJ 6小鼠的实验性糖尿病相关。这些变化在RAGE转基因小鼠中显著增强。糖尿病C57/BJ 6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。在糖尿病C57/BJ 6和RAGE转基因小鼠中，全身给予sodium显著抑制血-视网膜屏障破坏、白细胞停滞和视网膜中ICAM-1的表达。在糖尿病或RAGE转基因小鼠的视网膜血管中，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了强烈的视网膜色素变性诱导。本研究进一步证实了AGEs和视网膜电轴在血-视网膜屏障破坏和视网膜白细胞停滞中的作用，这是糖尿病视网膜病变的特征性临床症状。此外，这些数据表明，阻断AGE生物活性可能对治疗糖尿病视网膜病变有效。
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 mu g/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.