title: Complement activation contributes to both glomerular and tubulointerstitial damage in adriamycin nephropathy in mice.
abstract: Adriamycin nephropathy is a model of focal segmental glomerulosclerosis, characterized by proteinuria and progressive glomerulosclerosis and tubulointerstitial damage. In this study, we examined the role of complement in the etiology of adriamycin nephropathy in mice. We used mice deficient in C1q, factor D, C3, and CD59, and compared them with strain-matched controls. C3 deposition occurred in the glomeruli of wild-type mice as early as 48 h following a single i.v. injection of adriamycin. C3-deficient mice developed significantly less proteinuria and less podocyte injury at day 3 postadriamycin than controls, suggesting that complement is important in mediating the early podocyte injury. At later time points, C3-deficient mice were protected from glomerulosclerosis, tubulointerstitial injury, and renal dysfunction. Factor D-deficient mice were also protected from renal disease, confirming the importance of alternative pathway activation in this model. In contrast, C1q-deficient mice developed similar disease to controls, indicating that the complement cascade was not activated via the classical pathway. CD59-deficient mice, which lack adequate control of C5b-9 formation, developed significantly worse histological and functional markers of renal disease than controls. Interestingly, although more C9 deposited in glomeruli of CD59-deficient mice than controls, in neither group was tubulointerstitial C9 staining apparent. We have demonstrated for the first time that alternative pathway activation of complement plays an important role in mediating the initial glomerular damage in this in vivo model of focal segmental glomerulosclerosis. Lack of CD59, which regulates the membrane attack complex, led to greater glomerular and tubulointerstitial injury.
authors.affiliation: Rheumatology Section, Faculty of Medicine, Imperial College, Hammersmith Campus, London, United Kingdom.
authors.forename: Daniel
authors.initials: D
authors.lastname: Turnberg
authors.forename: Margarita
authors.initials: M
authors.lastname: Lewis
authors.forename: Jill
authors.initials: J
authors.lastname: Moss
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Xu
authors.forename: Marina
authors.initials: M
authors.lastname: Botto
authors.forename: H Terence
authors.initials: HT
authors.lastname: Cook
mesh_terms: D000818:Animals; D018957:CD59 Antigens / Q000235:genetics; D015922:Complement C1q / Q000172:deficiency; D050577:Complement C3-C5 Convertases / Q000172:deficiency; D011416:Complement Factor D / Q000172:deficiency; D003170:Complement Pathway, Alternative / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D003165:Complement System Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D004306:Dose-Response Relationship, Immunologic; D004317:Doxorubicin / Q000633:toxicity*; D005260:Female; D007678:Kidney Glomerulus / Q000187:drug effects / Q000276:immunology* / Q000473:pathology* / Q000648:ultrastructure; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009395:Nephritis, Interstitial / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000473:pathology*
chemical_list: D018957:CD59 Antigens; D004317:Doxorubicin; D015922:Complement C1q; D003165:Complement System Proteins; D050577:Complement C3-C5 Convertases; D011416:Complement Factor D