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

Yuichi Kaji, Tomohiko Usui, Susumu Ishida, Kenji Yamashiro, Tara Moore, Johnny Moore, Yasuhiko Yamamoto, Hiroshi Yamamoto, Anthony P. Adamis

Research output: Contribution to journalArticle

104 Citations (Scopus)

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 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.
LanguageEnglish
Pages858-865
JournalINVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE
Volume48
Issue number2
DOIs
Publication statusPublished - 1 Feb 2007

Fingerprint

Leukostasis
Blood-Retinal Barrier
Transgenic Mice
Diabetic Retinopathy
Intercellular Adhesion Molecule-1
Retina
Retinal Vessels
Vascular Endothelial Growth Factor A
Advanced Glycosylation End Products
Medical Genetics
Streptozocin
Serum Albumin
Advanced Glycosylation End Product-Specific Receptor
Injections
DNA

Cite this

Kaji, Yuichi ; Usui, Tomohiko ; Ishida, Susumu ; Yamashiro, Kenji ; Moore, Tara ; Moore, Johnny ; Yamamoto, Yasuhiko ; Yamamoto, Hiroshi ; Adamis, Anthony P. / Inhibition of diabetic leukostasis and blood-retinal barrier breakdown with a soluble form of a receptor for advanced glycation end products. In: INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE. 2007 ; Vol. 48, No. 2. pp. 858-865.
@article{76d3bb3452f94468b4de920ce546725b,
title = "Inhibition of diabetic leukostasis and blood-retinal barrier breakdown with a soluble form of a receptor for advanced glycation end products",
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 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.",
author = "Yuichi Kaji and Tomohiko Usui and Susumu Ishida and Kenji Yamashiro and Tara Moore and Johnny Moore and Yasuhiko Yamamoto and Hiroshi Yamamoto and Adamis, {Anthony P.}",
year = "2007",
month = "2",
day = "1",
doi = "10.1167/iovs.06-0495",
language = "English",
volume = "48",
pages = "858--865",
journal = "Investigative Ophthalmology and Visual Science",
issn = "0146-0404",
number = "2",

}

Inhibition of diabetic leukostasis and blood-retinal barrier breakdown with a soluble form of a receptor for advanced glycation end products. / Kaji, Yuichi; Usui, Tomohiko; Ishida, Susumu; Yamashiro, Kenji; Moore, Tara; Moore, Johnny; Yamamoto, Yasuhiko; Yamamoto, Hiroshi; Adamis, Anthony P.

In: INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, Vol. 48, No. 2, 01.02.2007, p. 858-865.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Inhibition of diabetic leukostasis and blood-retinal barrier breakdown with a soluble form of a receptor for advanced glycation end products

AU - Kaji, Yuichi

AU - Usui, Tomohiko

AU - Ishida, Susumu

AU - Yamashiro, Kenji

AU - Moore, Tara

AU - Moore, Johnny

AU - Yamamoto, Yasuhiko

AU - Yamamoto, Hiroshi

AU - Adamis, Anthony P.

PY - 2007/2/1

Y1 - 2007/2/1

N2 - 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.

AB - 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.

U2 - 10.1167/iovs.06-0495

DO - 10.1167/iovs.06-0495

M3 - Article

VL - 48

SP - 858

EP - 865

JO - Investigative Ophthalmology and Visual Science

T2 - Investigative Ophthalmology and Visual Science

JF - Investigative Ophthalmology and Visual Science

SN - 0146-0404

IS - 2

ER -