title: Inhibition of diabetic leukostasis and blood-retinal barrier breakdown with a soluble form of a receptor for advanced glycation end products.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Ophthalmology, University of Tsukuba, Institute of Clinical Medicine, Ibaraki, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Kaji
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Usui
authors.forename: Susumu
authors.initials: S
authors.lastname: Ishida
authors.forename: Kenji
authors.initials: K
authors.lastname: Yamashiro
authors.forename: Tara C B
authors.initials: TC
authors.lastname: Moore
authors.forename: Jonathan
authors.initials: J
authors.lastname: Moore
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamamoto
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Adamis
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D001813:Blood-Retinal Barrier; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000517:prevention & control; D003930:Diabetic Retinopathy / Q000378:metabolism / Q000517:prevention & control*; D005786:Gene Expression Regulation / Q000502:physiology*; D017127:Glycation End Products, Advanced / Q000097:blood; D007124:Immunoenzyme Techniques; D007274:Injections, Intraperitoneal; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D018921:Leukostasis / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000235:genetics*; D012160:Retina / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D017127:Glycation End Products, Advanced; C090509:Icam1 protein, mouse; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D018799:Intercellular Adhesion Molecule-1