Nephrotic syndrome and subepithelial deposits in a mouse model of immune-mediated anti-podocyte glomerulonephritis.

TY - JOUR

T1 - Nephrotic syndrome and subepithelial deposits in a mouse model of immune-mediated anti-podocyte glomerulonephritis.

AU - Meyer-Schwesinger, Catherine

AU - Dehde, Silke

AU - Klug, Philipp

AU - Becker, Jan U

AU - Mathey, Sabrina

AU - Arefi, Kazem

AU - Balabanov, Stefan

AU - Venz, Simone

AU - Endlich, Karl-Hans

AU - Pekna, Marcela

AU - Gessner, J Engelbert

AU - Thaiss, Friedrich

AU - Meyer, Tobias N

PY - 2011

Y1 - 2011

N2 - 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.

AB - 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.

KW - Animals

KW - Immunohistochemistry

KW - Disease Models, Animal

KW - Mice

KW - Mice, Inbred BALB C

KW - Mice, Inbred C57BL

KW - Reverse Transcriptase Polymerase Chain Reaction

KW - Immunoblotting

KW - Enzyme-Linked Immunosorbent Assay

KW - Microscopy, Electron, Transmission

KW - Electrophoresis, Gel, Two-Dimensional

KW - Antigen-Antibody Complex/immunology

KW - Autoantibodies/immunology

KW - Autoantigens/immunology

KW - Autoimmune Diseases/immunology/pathology

KW - Glomerulonephritis/immunology/pathology

KW - Microscopy, Immunoelectron

KW - Nephrotic Syndrome/immunology/pathology

KW - Podocytes/immunology/pathology

KW - Animals

KW - Immunohistochemistry

KW - Disease Models, Animal

KW - Mice

KW - Mice, Inbred BALB C

KW - Mice, Inbred C57BL

KW - Reverse Transcriptase Polymerase Chain Reaction

KW - Immunoblotting

KW - Enzyme-Linked Immunosorbent Assay

KW - Microscopy, Electron, Transmission

KW - Electrophoresis, Gel, Two-Dimensional

KW - Antigen-Antibody Complex/immunology

KW - Autoantibodies/immunology

KW - Autoantigens/immunology

KW - Autoimmune Diseases/immunology/pathology

KW - Glomerulonephritis/immunology/pathology

KW - Microscopy, Immunoelectron

KW - Nephrotic Syndrome/immunology/pathology

KW - Podocytes/immunology/pathology

M3 - SCORING: Journal article

VL - 187

SP - 3218

EP - 3229

JO - J IMMUNOL

JF - J IMMUNOL

SN - 0022-1767

IS - 6

M1 - 6

ER -