Autoimmunity in membranous nephropathy targets aldose reductase and SOD2.
Glomerular targets of autoimmunity in human membranous nephropathy are poorly understood. Here, we used a combined proteomic approach to identify specific antibodies against podocyte proteins in both serum and glomeruli of patients with membranous nephropathy (MN). We detected specific anti-aldose reductase (AR) and anti-manganese superoxide dismutase (SOD2) IgG(4) in sera of patients with MN. We also eluted high titers of anti-AR and anti-SOD2 IgG(4) from microdissected glomeruli of three biopsies of MN kidneys but not from biopsies of other glomerulonephritides characterized by IgG deposition (five lupus nephritis and two membranoproliferative glomerulonephritis). We identified both antigens in MN biopsies but not in other renal pathologies or normal kidney. Confocal and immunoelectron microscopy (IEM) showed co-localization of anti-AR and anti-SOD2 with IgG(4) and C5b-9 in electron-dense podocyte immune deposits. Preliminary in vitro experiments showed an increase of SOD2 expression on podocyte plasma membrane after treatment with hydrogen peroxide. In conclusion, our data support AR and SOD2 as renal antigens of human MN and suggest that oxidative stress may drive glomerular SOD2 expression.
Prunotto
Marco
M
Division of Nephrology and Laboratory on Pathophysiology of Uremia, G. Gaslini Children Hospital, Genova, Italy.
Carnevali
Maria Luisa
ML
Candiano
Giovanni
G
Murtas
Corrado
C
Bruschi
Maurizio
M
Corradini
Emilia
E
Trivelli
Antonella
A
Magnasco
Alberto
A
Petretto
Andrea
A
Santucci
Laura
L
Mattei
Silvia
S
Gatti
Rita
R
Scolari
Francesco
F
Kador
Peter
P
Allegri
Landino
L
Ghiggeri
Gian Marco
GM
D000328:Adult; D000368:Aged; D000449:Aldehyde Reductase / Q000276:immunology* / Q000378:metabolism; D000918:Antibody Specificity; D001323:Autoantibodies / Q000097:blood*; D001327:Autoimmune Diseases / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D001706:Biopsy; D015938:Complement Membrane Attack Complex / Q000378:metabolism; D005260:Female; D050533:Glomerular Basement Membrane / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015433:Glomerulonephritis, Membranous / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress / Q000276:immunology; D050199:Podocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D040901:Proteomics; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013482:Superoxide Dismutase / Q000276:immunology* / Q000378:metabolism; D000099156:Superoxide Dismutase 2
D000449:Aldehyde Reductase; D001323:Autoantibodies; D015938:Complement Membrane Attack Complex; D007074:Immunoglobulin G; D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2