title: Murine membranous nephropathy: immunization with α3(IV) collagen fragment induces subepithelial immune complexes and FcγR-independent nephrotic syndrome.
abstract: Membranous nephropathy (MN) is a leading cause of nephrotic syndrome in adults and a significant cause of end-stage renal disease, yet current therapies are nonspecific, toxic, and often ineffective. The development of novel targeted therapies requires a detailed understanding of the pathogenic mechanisms, but progress is hampered by the lack of a robust mouse model of disease. We report that DBA/1 mice as well as congenic FcγRIII(-/-) and FcRγ(-/-) mice immunized with a fragment of α3(IV) collagen developed massive albuminuria and nephrotic syndrome, because of subepithelial deposits of mouse IgG and C3 with corresponding basement membrane reaction and podocyte foot process effacement. The clinical presentation and histopathologic findings were characteristic of MN. Although immunized mice produced genuine anti-α3NC1 autoantibodies that bound to kidney and lung basement membranes, neither crescentic glomerulonephritis nor alveolitis ensued, likely because of the predominance of mouse IgG1 over IgG2a and IgG2b autoantibodies. The ablation of activating IgG Fc receptors did not ameliorate injury, implicating subepithelial deposition of immune complexes and consequent complement activation as a major effector pathway. We have thus established an active model of murine MN. This model, leveraged by the availability of genetically engineered mice and mouse-specific reagents, will be instrumental in studying the pathogenesis of MN and evaluating the efficacy of novel experimental therapies.
authors.affiliation: Division of Nephrology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Jun-Jun
authors.initials: JJ
authors.lastname: Zhang
authors.forename: Mahdi
authors.initials: M
authors.lastname: Malekpour
authors.forename: Wentian
authors.initials: W
authors.lastname: Luo
authors.forename: Linna
authors.initials: L
authors.lastname: Ge
authors.forename: Florina
authors.initials: F
authors.lastname: Olaru
authors.forename: Xu-Ping
authors.initials: XP
authors.lastname: Wang
authors.forename: Maimouna
authors.initials: M
authors.lastname: Bah
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Sado
authors.forename: Laurence
authors.initials: L
authors.lastname: Heidet
authors.forename: Sandra
authors.initials: S
authors.lastname: Kleinau
authors.forename: Agnes B
authors.initials: AB
authors.lastname: Fogo
authors.forename: Dorin-Bogdan
authors.initials: DB
authors.lastname: Borza
mesh_terms: D000419:Albuminuria / Q000209:etiology / Q000276:immunology; D000818:Animals; D001323:Autoantibodies / Q000276:immunology; D001324:Autoantigens / Q000276:immunology / Q000633:toxicity*; D001485:Basement Membrane / Q000276:immunology; D024141:Collagen Type IV / Q000276:immunology / Q000633:toxicity*; D003176:Complement C3 / Q000276:immunology; D004195:Disease Models, Animal; D015433:Glomerulonephritis, Membranous / Q000150:complications / Q000276:immunology*; D007114:Immunization; D007074:Immunoglobulin G / Q000276:immunology; D007668:Kidney / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D020297:Mice, Congenic; D008811:Mice, Inbred DBA; D009404:Nephrotic Syndrome / Q000209:etiology* / Q000276:immunology; D011650:Pulmonary Alveoli / Q000276:immunology; D017452:Receptors, IgG; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000633:toxicity
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D024141:Collagen Type IV; D003176:Complement C3; D007074:Immunoglobulin G; D017452:Receptors, IgG; D011993:Recombinant Fusion Proteins; C057112:type IV collagen alpha3 chain