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CD59, a Complement Regulatory Protein, Controls Choroidal Neovascularization in a Mouse Model of Wet-Type Age-Related Macular Degeneration¹

Nalini S. Bora^2,*, Sankaranarayanan Kaliappan^*, Purushottam Jha^*, Qin Xu^*, Baalasubramanian Sivasankar, Claire L. Harris, B. Paul Morgan and Puran S. Bora^2,*

^* Department of Ophthalmology, Jones Eye Institute, Pat and Willard Walker Eye Research Center, University of Arkansas for Medical Sciences, Little Rock, AR 72205; and Department of Medical Biochemistry and Immunology, School of Medicine, Cardiff University, Cardiff, United Kingdom

We have shown that membrane attack complex (MAC) formation via the activation of the alternative pathway plays a central role in the laser-induced choroidal neovascularization (CNV). This study was undertaken to understand the role of a complement regulatory protein, CD59, which controls MAC assembly and function, in this model. CNV was induced by laser photocoagulation in C57BL/6 and Cd59a^–/– mice using an argon laser. Animals from each group were sacrificed on day 1, 3, 5, and 7 postlaser. Retinal pigment epithelium-choroid-scleral tissue was examined to determine the incidence and size of CNV complex, and semiquantitative RT-PCR and Western blot analysis for CD59a was studied. Recombinant soluble mouse CD59a-IgG2a fusion (rsCD59a-Fc) protein was injected via i.p. or intravitreal routes 24 h before laser. Our results demonstrated that CD59a (both mRNA and protein) was down-regulated during laser-induced CNV. Cd59a^–/– mice developed CNV complex early in the disease process. Increased MAC deposition was also observed in these Cd59a^–/– mice. Administration of rsCD59a-Fc inhibited the development of CNV complex in the mouse model by blocking MAC formation and also inhibited expression of angiogenic growth factors. These data provide strong evidence that CD59a plays a crucial role in regulating complement activation and MAC formation essential for the release of growth factors that drive the development of laser-induced CNV in mice. Thus, our results suggest that the inhibition of complement by soluble CD59 may provide a novel therapeutic alternative to current treatment.

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 This work was supported in part by National Institutes of Health Grants EY014623 and EY13335, Research to Prevent Blindness, NY, and grants from University of Arkansas for Medical Sciences (Little Rock, AR). The use of the facilities in the University of Arkansas for Medical Sciences Digital and Confocal Microscopy Laboratory was supported by National Institutes of Health Grant 2P20 RR16460 and National Institutes of Health/National Center for Research Resources Grant 1 S10 RR 19395.

² Address correspondence and reprint requests to Dr. Puran S. Bora, Department of Ophthalmology, Jones Eye Institute, University of Arkansas for Medical Sciences, 4301 West Markham, Slot 523, Little Rock, AR 72205-7199; E-mail address: PBora{at}UAMS.edu or Dr. Nalini S. Bora, Department of Ophthalmology, Jones Eye Institute, University of Arkansas for Medical Sciences, 4301 West Markham, Slot 523, Little Rock, AR 72205-7199; E-mail address: NBora{at}UAMS.edu

³ Abbreviations used in this paper: AMD, age-related macular degeneration; CNV, choroidal neovascularization; BM, Bruch’s membrane; CReg, complement regulatory protein; MAC, membrane attack complex; RPE, retinal pigment epithelium; FGF, fibroblast growth factor; WT, wild type; VEGF, vascular endothelial growth factor.

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