title: Pigment epithelium-derived factor inhibits advanced glycation end product-induced retinal vascular hyperpermeability by blocking reactive oxygen species-mediated vascular endothelial growth factor expression.
abstract: Pigment epithelium-derived factor (PEDF) is the most potent inhibitor of angiogenesis, suggesting that loss of PEDF contributes to proliferative diabetic retinopathy. However, the role of PEDF against retinal vascular hyperpermeability remains to be elucidated. We investigated here whether and how PEDF could inhibit the advanced glycation end product (AGE) signaling to vascular hyperpermeability. Intravenous administration of AGEs to normal rats not only increased retinal vascular permeability by stimulating vascular endothelial growth factor (VEGF) expression but also decreased retinal PEDF levels. Simultaneous treatments with PEDF inhibited the AGE-elicited VEGF-mediated permeability by down-regulating mRNA levels of p22(phox) and gp91(phox), membrane components of NADPH oxidase, and subsequently decreasing retinal levels of an oxidative stress marker, 8-hydroxydeoxyguanosine. PEDF also inhibited the AGE-induced vascular hyperpermeability evaluated by transendothelial electrical resistance by suppressing VEGF expression. Furthermore, PEDF decreased reactive oxygen species (ROS) generation in AGE-exposed endothelial cells by suppressing NADPH oxidase activity via down-regulation of mRNA levels of p22(PHOX) and gp91(PHOX). This led to blockade of the AGE-elicited Ras activation and NF-kappaB-dependent VEGF gene induction in endothelial cells. These results indicate that the central mechanism for PEDF inhibition of the AGE signaling to vascular permeability is by suppression of NADPH oxidase-mediated ROS generation and subsequent VEGF expression. Substitution of PEDF may offer a promising strategy for halting the development of diabetic retinopathy.
authors.affiliation: Department of Internal Medicine III, Kurume University School of Medicine, Kurume 830-0011, Japan. shoichi@med.kurume-u.ac.jp
authors.forename: Sho-ichi
authors.initials: S
authors.lastname: Yamagishi
authors.forename: Kazuo
authors.initials: K
authors.lastname: Nakamura
authors.forename: Takanori
authors.initials: T
authors.lastname: Matsui
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Inagaki
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Takenaka
authors.forename: Yuko
authors.initials: Y
authors.lastname: Jinnouchi
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Yoshida
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Matsuura
authors.forename: Isao
authors.initials: I
authors.lastname: Narama
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Motomiya
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Takeuchi
authors.forename: Hiroyoshi
authors.initials: H
authors.lastname: Inoue
authors.forename: Akihiko
authors.initials: A
authors.lastname: Yoshimura
authors.forename: Richard
authors.initials: R
authors.lastname: Bucala
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Imaizumi
mesh_terms: D000328:Adult; D000818:Animals; D002199:Capillary Permeability / Q000502:physiology*; D003930:Diabetic Retinopathy / Q000503:physiopathology; D004594:Electrophysiology; D005136:Eye Proteins / Q000502:physiology*; D005260:Female; D017127:Glycation End Products, Advanced / Q000037:antagonists & inhibitors*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009414:Nerve Growth Factors / Q000502:physiology*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012016:Reference Values; D012171:Retinal Vessels / Q000502:physiology*; D015843:Serpins / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*; D000099174:Pigment Epithelium-Derived Factor
chemical_list: D005136:Eye Proteins; D017127:Glycation End Products, Advanced; D009414:Nerve Growth Factors; D017382:Reactive Oxygen Species; D015843:Serpins; D042461:Vascular Endothelial Growth Factor A; D000099174:Pigment Epithelium-Derived Factor