title: Pigment epithelium-derived factor (PEDF) prevents diabetes- or advanced glycation end products (AGE)-elicited retinal leukostasis.
abstract: Pigment epithelium-derived factor (PEDF) is the most potent inhibitor of angiogenesis in the mammalian eye, suggesting that PEDF may protect against proliferative diabetic retinopathy. However, a role for PEDF in early diabetic retinopathy remains to be elucidated. Leukocyte adhesion to retinal capillary endothelium (leukostasis) is a critical event in early diabetic retinopathy, whose process is mainly mediated by intercellular adhesion molecule-1 (ICAM-1). We investigated here whether PEDF could prevent diabetes- or advanced glycation end products (AGE)-elicited retinal leukostasis by suppressing ICAM-1 expression. Immunohistochemistry of 8-hydroxydeoxyguanosine (8-OHdG), an oxidative stress marker, showed intense staining in the nuclei of cells in the inner and outer plexiform layers of streptozotocin-induced diabetic rat retinas. Administration of PEDF or pyridoxal phosphate, an AGE inhibitor, decreased retinal levels of 8-OHdG and subsequently suppressed ICAM-1 gene expression and retinal leukostasis in diabetic rats. Further, intravenous administration of AGE to normal rats increased ICAM-1 gene expression and retinal leukostasis, which were blocked by PEDF. PEDF also inhibited the AGE-induced T cell adhesion to microvascular endothelial cells by suppressing ICAM-1 expression. These results demonstrated that PEDF inhibited diabetes- or AGE-elicited retinal leukostasis by suppressing ICAM-1. Our present study suggests that PEDF may play a protective role against early diabetic retinopathy by attenuating the deleterious effect of AGE.
authors.affiliation: Department of Internal Medicine III, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan. shoichi@med.kurume-u.ac.jp
authors.forename: Sho-ichi
authors.initials: S
authors.lastname: Yamagishi
authors.forename: Takanori
authors.initials: T
authors.lastname: Matsui
authors.forename: Kazuo
authors.initials: K
authors.lastname: Nakamura
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Takeuchi
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Imaizumi
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D002478:Cells, Cultured; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000494:pharmacology; D048909:Diabetes Complications; D003920:Diabetes Mellitus / Q000473:pathology*; D042783:Endothelial Cells / Q000166:cytology*; D005136:Eye Proteins / Q000502:physiology*; D017127:Glycation End Products, Advanced / Q000494:pharmacology*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D018921:Leukostasis / Q000378:metabolism / Q000517:prevention & control*; D008833:Microcirculation; D009414:Nerve Growth Factors / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012164:Retinal Diseases / Q000378:metabolism / Q000517:prevention & control*; D015843:Serpins / Q000502:physiology*; D000099174:Pigment Epithelium-Derived Factor
chemical_list: D000080242:8-Hydroxy-2'-Deoxyguanosine; D003849:Deoxyguanosine; D005136:Eye Proteins; D017127:Glycation End Products, Advanced; D018799:Intercellular Adhesion Molecule-1; D009414:Nerve Growth Factors; D015843:Serpins; D000099174:Pigment Epithelium-Derived Factor