Autoimmunity in Membranous Nephropathy Targets Aldose Reductase and SOD2

Abstract

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.

Anti-Phospholipase A2 Receptor Antibodies Correlate with Clinical Status in Idiopathic Membranous Nephropathy

“…Although the exact mechanisms and the role of PLA 2 R in pathogenesis of iMN are currently still unknown, these data strengthen the role of PLA 2 R as the major target antigen in iMN. Other recently described antigens may play a role in our anti-PLA 2 R-negative patients (6).…”

“…Accumulated evidence from the experimental rat model of Heymann nephritis and alloimmune membranous nephropathy (MN) from fetomaternal immunization to neutral endopeptidase has advanced the hypothesis that, in human MN, a circulating antibody reacts with and binds to a primary antigenic target on podocytes (1)(2)(3)(4). Further insights into the pathogenesis of human disease were established in the past few years, as several other podocyte target antigens have been proposed on the basis of the presence of circulating antibodies in patients with MN (5,6).…”

IgG subclass staining in renal biopsies with membranous glomerulonephritis indicates subclass switch during disease progression

“…[2][3][4] However, other potential antigens in primary/idiopathic membranous glomerulonephritis may also evoke an IgG4 response. [5][6][7][8] Also, one has to consider that the presence of an underlying condition, that can be associated with membranous glomerulonephritis, does not necessarily exclude the possibility of a primary membranous glomerulonephritis, particularly if the glomerular capillary deposits are IgG4 dominant (eg, a person with a malignancy or hepatitis B or C virus infection can have membranous glomerulonephritis independent of these conditions). Our data confirmed the already known fact that, in most biopsies with primary membranous glomerulonephritis, the glomerular deposits are IgG4 dominant.…”

Rituximab-based novel strategies for the treatment of immune-mediated glomerular diseases

“…The presence or absence of the antibody did not predict who would respond to therapy, however, and therefore should not influence whether a patient should receive RTX. There is also evidence that additional podocyte antigens, such as neutral endopeptidase (NEP) , aldose reductase (AR), SOD2 and α-enolase (α-ENO) may be the target of pathologic auto-antibodies in idiopathic membranous nephropathy [67], [68], [69] and [70]. A recent study examined the auto-antibody profile of 186 consecutive patients diagnosed with idiopathic membranous nephropathy [71], as well as of healthy controls and patients with other proteinuric diseases (FSGS and IgA nephropathy).…”