title: Nephrotic syndrome and subepithelial deposits in a mouse model of immune-mediated anti-podocyte glomerulonephritis.
abstract: Subepithelial immune complex deposition in glomerular disease causes local inflammation and proteinuria by podocyte disruption. A rat model of membranous nephropathy, the passive Heymann nephritis, suggests that Abs against specific podocyte Ags cause subepithelial deposit formation and podocyte foot process disruption. In this study, we present a mouse model in which a polyclonal sheep anti-mouse podocyte Ab caused subepithelial immune complex formation. Mice developed a nephrotic syndrome with severe edema, proteinuria, hypoalbuminemia, and elevated cholesterol and triglycerides. Development of proteinuria was biphasic: an initial protein loss was followed by a second massive increase of protein loss beginning at approximately day 10. By histology, podocytes were swollen. Electron microscopy revealed 60-80% podocyte foot process effacement and subepithelial deposits, but no disruption of the glomerular basement membrane. Nephrin and synaptopodin staining was severely disrupted, and podocyte number was reduced in anti-podocyte serum-treated mice, indicating severe podocyte damage. Immunohistochemistry detected the injected anti-podocyte Ab exclusively along the glomerular filtration barrier. Immunoelectron microscopy localized the Ab to podocyte foot processes and the glomerular basement membrane. Similarly, immunohistochemistry localized mouse IgG to the subepithelial space. The third complement component (C3) was detected in a linear staining pattern along the glomerular basement membrane and in the mesangial hinge region. However, C3-deficient mice were not protected from podocyte damage, indicating a complement-independent mechanism. Twenty proteins were identified as possible Ags to the sheep anti-podocyte serum by mass spectrometry. Together, these data establish a reproducible model of immune-mediated podocyte injury in mice with subepithelial immune complex formation.
authors.affiliation: Department of Internal Medicine, University Hospital Hamburg, Hamburg, Germany,
authors.forename: Catherine
authors.initials: C
authors.lastname: Meyer-Schwesinger
authors.forename: Silke
authors.initials: S
authors.lastname: Dehde
authors.forename: Philipp
authors.initials: P
authors.lastname: Klug
authors.forename: Jan U
authors.initials: JU
authors.lastname: Becker
authors.forename: Sabrina
authors.initials: S
authors.lastname: Mathey
authors.forename: Kazem
authors.initials: K
authors.lastname: Arefi
authors.forename: Stefan
authors.initials: S
authors.lastname: Balabanov
authors.forename: Simone
authors.initials: S
authors.lastname: Venz
authors.forename: Karl-Hans
authors.initials: KH
authors.lastname: Endlich
authors.forename: Marcela
authors.initials: M
authors.lastname: Pekna
authors.forename: J Engelbert
authors.initials: JE
authors.lastname: Gessner
authors.forename: Friedrich
authors.initials: F
authors.lastname: Thaiss
authors.forename: Tobias N
authors.initials: TN
authors.lastname: Meyer
mesh_terms: D000818:Animals; D000936:Antigen-Antibody Complex / Q000276:immunology; D001323:Autoantibodies / Q000276:immunology; D001324:Autoantigens / Q000276:immunology; D001327:Autoimmune Diseases / Q000276:immunology* / Q000473:pathology; D004195:Disease Models, Animal; D015180:Electrophoresis, Gel, Two-Dimensional; D004797:Enzyme-Linked Immunosorbent Assay; D005921:Glomerulonephritis / Q000276:immunology* / Q000473:pathology; D015151:Immunoblotting; D007150:Immunohistochemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D046529:Microscopy, Electron, Transmission; D016253:Microscopy, Immunoelectron; D009404:Nephrotic Syndrome / Q000276:immunology* / Q000473:pathology; D050199:Podocytes / Q000276:immunology* / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000936:Antigen-Antibody Complex; D001323:Autoantibodies; D001324:Autoantigens