Short CommunicationPigment epithelium-derived factor (PEDF) prevents diabetes- or advanced glycation end products (AGE)-elicited retinal leukostasis
Introduction
Pigment epithelium-derived factor (PEDF) was first purified from the conditioned media of human retinal pigment epithelial cells with neuronal differentiating activity (Tombran-Tink and Barnstable, 2003). Recently, PEDF has been shown to be the most potent inhibitor of angiogenesis in the mammalian eye; it inhibited retinal endothelial cell (EC) growth and migration and suppressed ischemia-induced retinal neovascularization (Tombran-Tink and Barnstable, 2003), suggesting that PEDF could protect against the development of proliferative diabetic retinopathy. However, a protective role for PEDF in early diabetic retinopathy is not fully understood.
Leukocyte adhesion to the capillary endothelium (leukostasis) is a critical event in early diabetic retinopathy, whose process is mainly mediated by intercellular adhesion molecule-1 (ICAM-1) expression (Miyamoto et al., 1999). Since advanced glycation end products (AGE) participate in early diabetic retinopathy as well (Yamagishi and Imaizumi, 2005), we investigated here whether PEDF could inhibit diabetes- or AGE-elicited retinal leukostasis by suppressing ICAM-1 expression.
Section snippets
Materials
N-acetylcysteine (NAC) and 2-mercaptoethanol were purchased from Sigma (St. Louis, MO, USA). GeneAmp RNA PCR Core Kit was from Applied Biosystems (Branchburg, NJ, USA). A fluorescence dye, 3′-O-acetyl-2′,7′-bis(carboxyethyl)-4 or 5-carboxyfluorescein, diacetoxymethyl ester (BCECF-AM) was from DOJINDO Laboratories, Kumamoto, Japan.
Purification of PEDF proteins
PEDF proteins were purified as described previously (Yamagishi et al., 2002). SDS-PAGE analysis of purified PEDF proteins revealed a single band with a molecular
Results
Oxidative stress could contribute to retinal leukostasis in early diabetic retinopathy via ICAM-1 expression (Abiko et al., 2003). So, we first examined the effects of PEDF on retinal levels of 8-OHdG, an oxidative stress marker, ICAM-1 gene expression and retinal leukostasis in streptozotocin-induced diabetic rats. As shown in Fig. 1A, immunohistochemistry of 8-OHdG showed intense staining in the nuclei of cells in the inner and outer plexiform layers of diabetic rat retinas. Administration of
Discussion
One early phase of diabetic retinopathy involves the firm adhesion of inflammatory cells to retinal capillary endothelium (leukostasis) (Miyamoto et al., 1999). This process is predominantly mediated by cellular adhesion molecule, ICAM-1 (Miyamoto et al., 1999). Indeed, ICAM-1 blockage by monoclonal Abs significantly prevents retinal leukostasis and vascular leakage in experimental diabetic retinopathy (Miyamoto et al., 1999). Further, diabetic mice deficient in the genes encoding for ICAM-1
Acknowledgments
This study was supported in part by Grants of Venture Research and Development Centers from the Ministry of Education, Cultures, Sports, Science and Technology, Japan (S.Y.).
References (10)
- et al.
Pigment epithelium-derived factor protects cultured retinal pericytes from advanced glycation end product-induced injury through its antioxidative properties
Biochem. Biophys. Res. Commun.
(2002) - et al.
Characterization of retinal leukostasis and hemodynamics in insulin resistance and diabetes: role of oxidants and protein kinase-C activation
Diabetes
(2003) - et al.
Low content of the natural ocular anti-angiogenic agent pigment epithelium-derived factor (PEDF) in aqueous humor predicts progression of diabetic retinopathy
Diabetologia
(2003) - et al.
VEGF165 is proinflammatory in the diabetic retina
Invest. Ophthalmol. Visual Sci.
(2003) - et al.
A central role for inflammation in the pathogenesis of diabetic retinopathy
FASEB J.
(2004)
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