title: Respective roles of decay-accelerating factor and CD59 in circumventing glomerular injury in acute nephrotoxic serum nephritis.
abstract: Decay-accelerating factor (DAF or CD55) and CD59 are regulators that protect self cells from C3b deposition and C5b-9 assembly on their surfaces. Their relative roles in protecting glomeruli in immune-mediated renal diseases in vivo are unknown. We induced nephrotoxic serum (NTS) nephritis in Daf1(-/-), CD59a(-/-), Daf1(-/-)CD59a(-/-), and wild-type (WT) mice by administering NTS IgG. After 18 h, we assessed proteinuria, and performed histological, immunohistochemical, and electron microscopic analyses of kidneys. Twenty-four mice in each group were studied. Baseline albuminuria in the Daf1(-/-), CD59a(-/-), and Daf1(-/-)CD59a(-/-) mice was 82, 83, and 139 as compared with 92 microg/mg creatinine in the WT controls (p > 0.1). After NTS, albuminuria in CD59a(-/-) and WT mice (186 +/- 154 and 183 +/- 137 microg/mg creatinine, p > 0.1) was similar. In contrast, Daf1(-/-) mice developed severe albuminuria (378 +/- 520, p < 0.05) that was further exacerbated in Daf1(-/-)CD59a(-/-) mice (577 +/- 785 micro g/mg creatinine, p < 0.05). Glomerular histology showed essentially no infiltrating leukocytes in any group. In contrast, electron microscopy revealed prominent podocyte foot process effacement in Daf1(-/-) mice with more widespread and severe damage in the double knockouts compared with only mild focal changes in CD59a(-/-) or WT mice. In all animals, deposition of administered (sheep) NTS Ig was equivalent. This contrasted with marked deposition of both C3 and C9 in Daf1(-/-)CD59a(-/-) and Daf1(-/-) mice, which was evident as early as 2 h post-NTS injection. The results support the proposition that in autoantibody-mediated nephritis, DAF serves as the primary barrier to classical pathway-mediated injury, while CD59 limits consequent C5b-9-mediated cell damage.
authors.affiliation: Institute of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Lin
authors.forename: David J
authors.initials: DJ
authors.lastname: Salant
authors.forename: Howard
authors.initials: H
authors.lastname: Meyerson
authors.forename: Steven
authors.initials: S
authors.lastname: Emancipator
authors.forename: B Paul
authors.initials: BP
authors.lastname: Morgan
authors.forename: M Edward
authors.initials: ME
authors.lastname: Medof
mesh_terms: D000208:Acute Disease; D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology / Q000473:pathology; D018958:CD55 Antigens / Q000235:genetics / Q000502:physiology*; D018957:CD59 Antigens / Q000235:genetics / Q000502:physiology*; D003176:Complement C3 / Q000378:metabolism; D003186:Complement C9 / Q000378:metabolism; D003171:Complement Pathway, Classical / Q000235:genetics; D005455:Fluorescent Antibody Technique; D005921:Glomerulonephritis / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D007106:Immune Sera / Q000633:toxicity; D007678:Kidney Glomerulus / Q000276:immunology* / Q000473:pathology* / Q000648:ultrastructure; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011507:Proteinuria / Q000235:genetics / Q000276:immunology / Q000473:pathology
chemical_list: D018958:CD55 Antigens; D018957:CD59 Antigens; D003176:Complement C3; D003186:Complement C9; D007106:Immune Sera