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      Anti-Mouse Mesangial Cell Serum Induces Acute Glomerulonephropathy in Mice

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          In order to develop a model in mouse similar to anti- Thy-1 nephritis in the rat, we prepared sheep antiserum against SV40-transformed mouse mesangial (MES 13) cells. In vivo, the anti-mouse mesangial cell serum-treated mice showed severe azotemia that peaked at day 6 and proteinuria that peaked at day 8, in a dose-dependent fashion. Light microscopy and electron microscopy showed duplication of glomerular basement membranes, mesangiolysis, subendothelial and mesangial electron-dense deposits, and foot process effacement. Intraglomerular tuft cell number was significantly reduced at day 4 and there were increased numbers of apoptotic cells at days 2 and 4. SCID mice and mice lacking C3 manifested similar responses to anti-mouse mesangial cell serum, suggesting that T cells, B cells and complement are not required for glomerular injury in this model. In vitro, anti-mouse mesangial cell serum treated mesangial cells showed greater release of lactate dehydrogenase, decreased cell survival, and increased apoptotic cell death. Anti-mouse mesangial cell serum induces glomerulopathy characterized by mesangiolysis and mesangial cell apoptosis, and followed by cellular proliferation.

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          Fcγ Receptor Iib–Deficient Mice Develop Goodpasture's Syndrome upon Immunization with Type IV Collagen

          The combination of hemorrhagic pneumonitis and rapidly progressive glomerulonephritis is a characteristic feature of Goodpasture's syndrome (GPS), an autoimmune disease resulting from the interaction of pathogenic anti–collagen type IV (C-IV) antibodies with alveolar and glomerular basement membranes. Lack of a suitable animal model for this fatal disease has hampered both a basic understanding of its etiology and the development of therapeutic strategies. We now report a novel model for GPS using mice deficient in a central regulatory receptor for immunoglobulin (Ig)G antibody expression and function, the type IIB Fc receptor for IgG (FcγRIIB). Mutant mice immunized with bovine C-IV reproducibly develop massive pulmonary hemorrhage with neutrophil and macrophage infiltration and crescentic glomerulonephritis. The distinctive linear, ribbon-like deposition of IgG immune complex seen in GPS was observed along the glomerular and tubulointerstitial membranes of diseased animals. These results highlight the role of FcγRIIB in maintaining tolerance and suggest that it may play a role in the pathogenesis of human GPS.
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            Glomerular inflammation: use of genetically deficient mice to elucidate the roles of leukocyte adhesion molecules and Fc-gamma receptors in vivo.

            Single gene knock-outs in mice have been used to define the biological role of leukocyte adhesion receptors, Fc-gamma receptors and complement in animal models of immune complex glomerulonephritis. These studies have shown important differences in the role of P-selectin in glomerular inflammation and inflammation at other sites, and have given a new appreciation of the dominant role played by Fc-gamma receptors in immune complex-induced glomerular injury.
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              Altered distribution of intraglomerular immune complexes in C3-deficient mice.

              We have studied the role of complement in a model of glomerular inflammation induced by the in situ formation of immune complexes along the glomerular basement membrane. In C3-deficient mice, produced by homologous recombination, immune complex formation occurs initially in the subendothelial site and progresses slowly to the subepithelial position, whereas wild-type mice do not develop subendothelial deposits. In addition, the accumulation of electron-dense deposits is greater in the complement-deficient mice. Complement therefore influences glomerular handling of immune complexes, possibly because of changes in the physiochemical characteristics of the immune complexes. However, despite evidence of complement activation in the wild-type mice, as demonstrated by immunohistochemical detection of C3, C4 and C9, the degree of proteinuria was similar in C3-deficient mice. We conclude that, although complement is required for the normal glomerular metabolism of immune complexes, other, complement-independent, factors are involved in the generation of glomerular injury in this model.

                Author and article information

                Nephron Exp Nephrol
                Cardiorenal Medicine
                S. Karger AG
                March 2003
                17 November 2004
                : 93
                : 3
                : e92-e106
                aKidney Disease Section, National Institute of Diabetes and Digestive and Kidney Diseases, bMucosal Immunity Section, National Institute of Allergy and Infectious Diseases, and cVeterinary Resource Program, National Institutes of Health, Bethesda, Md., USA
                69551 Nephron Exp Nephrol 2003;93:e92–e106
                © 2003 S. Karger AG, Basel

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                Page count
                Figures: 10, References: 48, Pages: 1
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/69551
                Original Paper

                Cardiovascular Medicine, Nephrology

                Cell proliferation, Apoptosis, Nephrotoxic serum


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