title: Anti-vitronectin antibodies enhance anti-Thy-1-induced proteinuria in PVG/c, but not in Wistar rats.
abstract: Injection of rats with mouse monoclonal IgG2a anti-Thy1.1 antibodies (ER4G) results in rapid development of proteinuria in Wistar rats, reaching average values of 160 mg/24 h on day 3 after antibody administration. In contrast, no overt proteinuria was observed in PVG/c+ rats (maximum, 40 mg/24 h on day 3). This study investigates whether differences in the inactivation of C5b-9 complexes in the glomerulus by complement inhibitors are responsible for the differences in proteinuria between the two rat strains. Regardless of the presence of proteinuria, an increased expression of Crry by mesangial cells (MC) was observed within 24 h after injection of ER4G in both Wistar and PVG/c+ rats. Double-label immunofluorescence using goat anti-mouse Ig antibodies demonstrated an expression of Crry exclusively on MC. Furthermore, Crry colocalized with C5b-9 complexes on MC, as detected by a monoclonal antibody against the rat C5b-9 neo-antigen. In PVG/c+ rats, C5b-9 complexes persisted in the mesangial area for at least 7 d and colocalized immediately (within 1 h) and homogeneously with vitronectin. However, in proteinuric Wistar rats, C5b-9 complexes disappeared from the glomerular mesangium within 6 d. In these rats, mesangial colocalization of C5b-9 with vitronectin could only occasionally be detected. Pretreatment of PVG/c+ rats with antibodies against vitronectin, followed by administration of ER4G, resulted in the immediate development of proteinuria (maximum, 119 mg/24 h on day 3; P < 0.05), whereas Wistar rats did not become more proteinuric. This study provides evidence that differences in susceptibility of PVG/c+ and Wistar rats to complement-mediated damage of the glomerulus may be related to the degree of inactivation of C5b-9 complexes by complement regulatory factors.
authors.affiliation: Department of Nephrology, Leiden University Hospital, The Netherlands.
authors.forename: M G
authors.initials: MG
authors.lastname: Van Dixhoorn
authors.forename: D
authors.initials: D
authors.lastname: Salazar-Exaire
authors.forename: T
authors.initials: T
authors.lastname: Sato
authors.forename: M R
authors.initials: MR
authors.lastname: Daha
authors.forename: R J
authors.initials: RJ
authors.lastname: Quigg
authors.forename: J A
authors.initials: JA
authors.lastname: Bruijn
authors.forename: W G
authors.initials: WG
authors.lastname: Couser
authors.forename: E
authors.initials: E
authors.lastname: De Heer
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000494:pharmacology*; D000954:Antigens, Surface; D018958:CD55 Antigens / Q000276:immunology; D015938:Complement Membrane Attack Complex / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000473:pathology; D007678:Kidney Glomerulus / Q000378:metabolism; D008297:Male; D051379:Mice; D009393:Nephritis / Q000276:immunology / Q000473:pathology / Q000652:urine; D011507:Proteinuria / Q000276:immunology* / Q000473:pathology; D051381:Rats; D011919:Rats, Inbred Strains / Q000502:physiology*; D017208:Rats, Wistar; D011956:Receptors, Cell Surface; D011951:Receptors, Complement / Q000378:metabolism; D017463:Receptors, Complement 3b; D013045:Species Specificity; D018800:Thy-1 Antigens / Q000276:immunology*; D019096:Vitronectin / Q000276:immunology* / Q000502:physiology
chemical_list: D000911:Antibodies, Monoclonal; D000954:Antigens, Surface; D018958:CD55 Antigens; D015938:Complement Membrane Attack Complex; C081470:Cr1l protein, mouse; C513105:Cr1l protein, rat; D011956:Receptors, Cell Surface; D011951:Receptors, Complement; D017463:Receptors, Complement 3b; D018800:Thy-1 Antigens; D019096:Vitronectin