title: Decreased membrane complement regulators in the retinal pigmented epithelium contributes to age-related macular degeneration.
abstract: Dysregulated complement is thought to play a central role in age-related macular degeneration (AMD) pathogenesis, but the specific mechanisms have yet to be determined. In maculae of AMD specimens, we found that the complement regulatory protein, CD59, was increased in regions of uninvolved retinal pigmented epithelium (RPE) of early AMD, but decreased in the RPE overlying drusen and in geographic atrophy, an advanced form of AMD. While CD46 immunostaining was basolaterally distributed in the RPE of unaffected controls, it was decreased in diseased areas of early AMD samples. Since oxidized low-density lipoproteins (oxLDL) collect in drusen of AMD and are a known complement trigger, we treated ARPE-19 cells with oxLDL and found that cellular CD46 and CD59 proteins were decreased by 2.9- and nine-fold (p < 0.01), respectively. OxLDLs increased complement factor B mRNA and Bb protein, but not factor D, I or H. OxLDLs increased C3b, but not C3a, C5 or C5b-9. C5b-9 was increased by 27% (p < 0.01) when the medium was supplemented with human serum, which was sufficient to induce poly(ADP-ribose) polymerase cleavage, a marker of apoptosis. The decreased levels of CD46 and CD59 were in part explained by their release in exosomal and apoptotic membranous particles. In addition, CD59 was partially degraded through activation of IRE1α. Collectively, these results suggest that a combination of impaired complement regulators results in inadequately controlled complement by the RPE in AMD that induces RPE damage.
authors.affiliation: Wilmer Eye Institute, Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: Katayoon B
authors.initials: KB
authors.lastname: Ebrahimi
authors.forename: Natalia
authors.initials: N
authors.lastname: Fijalkowski
authors.forename: Marisol
authors.initials: M
authors.lastname: Cano
authors.forename: James T
authors.initials: JT
authors.lastname: Handa
mesh_terms: D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis; D018957:CD59 Antigens / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002462:Cell Membrane / Q000276:immunology* / Q000473:pathology; D003167:Complement Activation; D003165:Complement System Proteins / Q000235:genetics / Q000378:metabolism*; D018450:Disease Progression; D015536:Down-Regulation; D004722:Endoribonucleases / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000276:immunology* / Q000473:pathology; D055354:Exosomes / Q000378:metabolism; D005260:Female; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism; D008268:Macular Degeneration / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008297:Male; D051916:Membrane Cofactor Protein / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D015593:Retinal Drusen / Q000276:immunology / Q000473:pathology; D055213:Retinal Pigment Epithelium / Q000276:immunology* / Q000473:pathology; D014162:Transfection; D055815:Young Adult
chemical_list: C497857:CD46 protein, human; D018957:CD59 Antigens; D008077:Lipoproteins, LDL; D051916:Membrane Cofactor Protein; D008565:Membrane Proteins; D012333:RNA, Messenger; C099252:oxidized low density lipoprotein; C051590:CD59 protein, human; D003165:Complement System Proteins; D011065:Poly(ADP-ribose) Polymerases; C403982:ERN2 protein, human; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases