CD59, a complement regulatory protein, controls choroidal neovascularization in a mouse model of wet-type age-related macular degeneration.
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.
Bora
Nalini S
NS
Department of Ophthalmology, Jones Eye Institute, Pat and Willard Walker Eye Research Center, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA. NBora@UAMS.edu
Kaliappan
Sankaranarayanan
S
Jha
Purushottam
P
Xu
Qin
Q
Sivasankar
Baalasubramanian
B
Harris
Claire L
CL
Morgan
B Paul
BP
Bora
Puran S
PS
D000818:Animals; D018957:CD59 Antigens / Q000032:analysis / Q000235:genetics / Q000502:physiology* / Q000627:therapeutic use; D020256:Choroidal Neovascularization / Q000188:drug therapy / Q000209:etiology*; D003167:Complement Activation; D015938:Complement Membrane Attack Complex; D004195:Disease Models, Animal; D015536:Down-Regulation; D007074:Immunoglobulin G / Q000235:genetics; D036341:Intercellular Signaling Peptides and Proteins; D007834:Lasers / Q000009:adverse effects; D008268:Macular Degeneration / Q000209:etiology / Q000473:pathology* / Q000628:therapy; D051379:Mice; D018345:Mice, Knockout; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000494:pharmacology
D018957:CD59 Antigens; D015938:Complement Membrane Attack Complex; D007074:Immunoglobulin G; D036341:Intercellular Signaling Peptides and Proteins; D011993:Recombinant Fusion Proteins