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J. Biol. Chem., Vol. 281, Issue 29, 20213-20220, July 21, 2006

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Pigment Epithelium-derived Factor Inhibits Advanced Glycation End Product-induced Retinal Vascular Hyperpermeability by Blocking Reactive Oxygen Species-mediated Vascular Endothelial Growth Factor Expression^*

Sho-ichi Yamagishi¹, Kazuo Nakamura, Takanori Matsui, Yosuke Inagaki, Katsuhiko Takenaka, Yuko Jinnouchi, Yumiko Yoshida, Tetsuro Matsuura, Isao Narama, Yoshihiro Motomiya^¶, Masayoshi Takeuchi^||, Hiroyoshi Inoue^**, Akihiko Yoshimura, Richard Bucala, and Tsutomu Imaizumi

From the Department of Internal Medicine III and ^**Radioisotope Institute for Basic and Clinical Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan, the Department of Pathology, Faculty of Pharmaceutical Science, Setsunan University, Hirakata 573-000, Japan, ^¶Suiyukai Clinic, Kashihara 634-000, Japan, the ^||Department of Pathophysiological Science, Faculty of Pharmaceutical Science, Hokuriku University, Kanazawa 920-1181, Japan, the Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-0054, Japan, and the Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520-8031

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-B-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.

Received for publication, March 6, 2006 , and in revised form, May 1, 2006.

^* This work was supported in part by Grants of Collaboration with Venture Companies Project from the Ministry of Education, Culture, Sports, Science and Technology, Japan (to S. Y.), the Specific Research Fund of Hokuriku University, Japan (to M. T.), and Creation and Support Program for Startups for Universities from Japan Science and Technology Agency, Japan (to H. I.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Internal Medicine III, Kurume University School of Medicine, 67 Asahi-machi, Kurume 830-0011, Japan. Tel.: 81-942-31-7580; Fax: 81-942-31-7707; E-mail: shoichi{at}med.kurume-u.ac.jp.

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