title: Pigment epithelium-derived factor reduces apoptosis and pro-inflammatory cytokine gene expression in a murine model of focal retinal degeneration.
abstract: AMD (age-related macular degeneration) is a neurodegenerative disease causing irreversible central blindness in the elderly. Apoptosis and inflammation play important roles in AMD pathogenesis. PEDF (pigment epithelium-derived factor) is a potent neurotrophic and anti-inflammatory glycoprotein that protects the retinal neurons and photoreceptors against cell death caused by pathological insults. We studied the effects of PEDF on focal retinal lesions in DKO rd8 (Ccl2(-/-)/Cx3cr1(-/-) on C57BL/6N [Crb1(rd8)]) mice, a model for progressive, focal rd (retinal degeneration). First, we found a significant decrease in PEDF transcript expression in DKO rd8 mouse retina and RPE (retinal pigment epithelium) than WT (wild-type, C57BL/6N). Next, cultured DKO rd8 RPE cells secreted lower levels of PEDF protein in the media than WT. Then the right eyes of DKO rd8 mice were injected intravitreously with recombinant human PEDF protein (1 μg), followed by a subconjunctival injection of PEDF (3 μg) 4 weeks later. The untreated left eyes served as controls. The effect of PEDF was assessed by fundoscopy, ocular histopathology and A2E {[2,6-dimethyl-8-(2,6,6-trimethyl-1-cyclohexen-1-yl)-1E,3E,5E,7E-octatetra-enyl]-1-(2-hydroxyethyl)-4-[4-methyl-6(2,6,6-trimethyl-1-cyclohexen-1-yl) 1E,3E,5E,7E-hexatrienyl]-pyridinium} levels, as well as apoptotic and inflammatory molecules. The PEDF-treated eyes showed slower progression or attenuation of the focal retinal lesions, fewer and/or smaller photoreceptor and RPE degeneration, and significantly lower A2E, relative to the untreated eyes. In addition, lower expression of apoptotic and inflammatory molecules were detected in the PEDF-treated than untreated eyes. Our results establish that PEDF potently stabilizes photoreceptor degeneration via suppression of both apoptotic and inflammatory pathways. The multiple beneficial effects of PEDF represent a novel approach for potential AMD treatment.
authors.forename: Yujuan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: ‡Section of Protein Structure and Function, Laboratory of Retinal Cell and Molecular Biology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, U.S.A.
authors.forename: Preeti
authors.initials: P
authors.lastname: Subramanian
authors.affiliation: *Immunopathology Section, Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, U.S.A.
authors.forename: Defen
authors.initials: D
authors.lastname: Shen
authors.affiliation: *Immunopathology Section, Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, U.S.A.
authors.forename: Jingsheng
authors.initials: J
authors.lastname: Tuo
authors.affiliation: ‡Section of Protein Structure and Function, Laboratory of Retinal Cell and Molecular Biology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, U.S.A.
authors.forename: S Patricia
authors.initials: SP
authors.lastname: Becerra
authors.affiliation: *Immunopathology Section, Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, U.S.A.
authors.forename: Chi-Chao
authors.initials: CC
authors.lastname: Chan
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D000073883:CX3C Chemokine Receptor 1; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005136:Eye Proteins / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009414:Nerve Growth Factors / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D009419:Nerve Tissue Proteins / Q000235:genetics; D011726:Pyridinium Compounds / Q000378:metabolism; D019707:Receptors, Chemokine / Q000235:genetics; D012160:Retina / Q000166:cytology; D012162:Retinal Degeneration / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D012176:Retinoids / Q000378:metabolism; D015843:Serpins / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D000099174:Pigment Epithelium-Derived Factor
chemical_list: D000893:Anti-Inflammatory Agents; D000073883:CX3C Chemokine Receptor 1; D018932:Chemokine CCL2; D016207:Cytokines; D005136:Eye Proteins; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D011726:Pyridinium Compounds; D019707:Receptors, Chemokine; D012176:Retinoids; D015843:Serpins; D000099174:Pigment Epithelium-Derived Factor; C112040:A2-E (N-retinylidene-N-retinylethanolamine); C491768:Ccl2 protein, mouse; C453730:Crb1 protein, mouse; C471885:Cx3cr1 protein, mouse