Proteomics of human glomerulonephritis by laser microdissection and liquid chromatography‐tandem mass spectrometry

Kawata, Naoto; Kang, Dedong; Aiuchi, Toshihiro; Obama, Takashi; Yoshitake, Osamu; Shibata, Takanori; Takimoto, Masafumi; Itabe, Hiroyuki; Honda, Kazuho

doi:10.1111/nep.13676

Cited by 25 publications

(34 citation statements)

References 23 publications

(42 reference statements)

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“…In the latter configuration, one complex contains two streptavidins with up to 4 × 2 − 1 = 7 dimeric IgAs attached to them (supplementary material, Figure S14). It should also be noted that not only can natural IgA be detected in their complex forms [56,57], but our uninduced IgA analog also spontaneously aggregates into oligomers (supplementary material, Figure S15). For animal injection experiments, we had purposely repurified mono‐rIgA immediately before injecting it into rats, and there was no renal deposition from mono‐rIgA, in contrast to SA‐induced poly‐rIgA which readily formed renal deposits.…”

Section: Discussionmentioning

confidence: 99%

Renal deposition and clearance of recombinant poly‐IgA complexes in a model of IgA nephropathy

Xie

Liu

Gao

et al. 2021

The Journal of Pathology

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IgA nephropathy (IgAN) is the most common type of glomerulonephritis worldwide, which follows a chronic but nonetheless highly variable course of progression. IgA immune complexes are the primary source of renal deposits in IgAN. Apart from the presence of granular IgA1 deposits in the glomerular mesangium and mesangial hypercellularity as common features, the detailed process of IgA1 deposition and clearance in the kidney remains unclear. We sought to examine the dynamics of IgA deposition and tissue plasticity in response to deposits including their intrarenal clearance. We followed a synthetic approach to produce a recombinant fusion between IgA Fc (rIgA) and a biotin tag, which was subsequently induced with streptavidin (SA) to form an oligomeric poly‐IgA mimic. Both uninduced rIgA (mono‐rIgA) and polymeric SA‐rIgA (poly‐rIgA) were injected intravenously into Wistar rats. Plasma IgA levels and renal and liver histology were examined in a time series. In contrast to mono‐rIgA, this synthetic poly‐rIgA analog formed renal deposits exclusively in the glomerulus and were mostly cleared in 3 h. However, repeated daily injections for 12 days caused long‐lasting and stronger glomerular IgA deposition together with IgG and complement C3, in association with mesangial cell proliferation, matrix expansion, and variable degrees of albuminuria and hematuria that phenocopied IgAN. Ex vivo, poly‐rIgA bound cultured mesangial cells and elicited cytokine production, in addition to activating plasma C3 that was consistent with the actions of IgA immune complexes in IgAN pathogenesis. Remarkably, the kidneys were able to reverse all pathologic manifestations and restore normal glomerular histology 2 weeks after injections were halted. The synthetic model showed the kinetics between the intricate balance of renal deposition and clearance, as well as glomerular plasticity towards healing. Together, the results revealed a priming effect of existing deposits in promoting stronger and longer‐lasting IgA deposition to cause renal damage. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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Section: Discussionmentioning

confidence: 99%

Renal deposition and clearance of recombinant poly‐IgA complexes in a model of IgA nephropathy

Xie

Liu

Gao

et al. 2021

The Journal of Pathology

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“…In studies by Kawata et al 8 and Ravindran et al 9 , peptide identi cations were accepted at greater than 95% probability, and the proteins identi ed had at least 2 matching peptides. In our proteomic analysis, principal component analysis demonstrated a different distribution between the pMN and sMN groups (Figure 1).…”

Section: Discussionmentioning

confidence: 99%

Proteomic Analysis of Glomerular Proteins in Primary and Bucillamine-induced Membranous Nephropathy

Kaga

Matsumura

Suzuki³

et al. 2021

Preprint

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The aim of this study was to characterize glomerular proteins in primary membranous nephropathy (pMN) and drug-induced secondary MN (sMN) by laser microdissection and comparative proteomic analysis. We used renal biopsy specimens from 6 patients with anti-phospholipase A2 receptor autoantibody (PLA2R Ab) (+) pMN, 6 patients with PLA2R Ab (‒) pMN, 6 patients with bucillamine (BCL)-induced sMN, and 5 control cases (time 0 transplant biopsies). Proteins were extracted from laser-microdissected glomeruli and analyzed using mass spectrometry. The quantification values of protein abundance in each MN group were compared with those in the control group. More than 800 proteins with high confidence were identified. Principal component analysis revealed a different distribution between the pMN and sMN groups. For further analysis, 441 proteins matched with ≥3 peptides were selected. Among the pMN and sMN groups, we compared the profiles of several protein groups based on the structural and functional characteristics, such as immunoglobulins, complements, complement-regulating proteins, podocyte-associated proteins, glomerular basement membrane proteins, and several proteins that are known to be associated with kidney diseases, including MN. Between the pMN and BCL-induced sMN groups, we observed common and different alterations in protein levels such as known disease-associated proteins and potential disease marker proteins.

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“…Additionally, immunization with human recombinant non-collagenous domain 1 (rh-α3NC1) led to the development of proteinuria and the deposition of C3 and C5b-9 in wild type mice but not in mice with AP deficiency [ 90 ]. In patients with PLA2R-associated PMN, the accumulation of C3 and C5b-9 in immune deposits occurs [ 91 , 92 ]. Both aPLA2R-Ab and aTHSD7A-Ab are predominant IgG4s [ 11 , 12 ], a subtype IgG that does not fix component C1q and thus is unable to initiate complement activation through the classical pathway (CP) [ 89 ].…”

Section: Mechanisms Underlying Pla2r- and Thsd7a-contributed Mn Pathogenesismentioning

confidence: 99%

Mechanisms of Primary Membranous Nephropathy

Tang

2021

Biomolecules

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Membranous nephropathy (MN) is an autoimmune disease of the kidney glomerulus and one of the leading causes of nephrotic syndrome. The disease exhibits heterogenous outcomes with approximately 30% of cases progressing to end-stage renal disease. The clinical management of MN has steadily advanced owing to the identification of autoantibodies to the phospholipase A2 receptor (PLA2R) in 2009 and thrombospondin domain-containing 7A (THSD7A) in 2014 on the podocyte surface. Approximately 50–80% and 3–5% of primary MN (PMN) cases are associated with either anti-PLA2R or anti-THSD7A antibodies, respectively. The presence of these autoantibodies is used for MN diagnosis; antibody levels correlate with disease severity and possess significant biomarker values in monitoring disease progression and treatment response. Importantly, both autoantibodies are causative to MN. Additionally, evidence is emerging that NELL-1 is associated with 5–10% of PMN cases that are PLA2R- and THSD7A-negative, which moves us one step closer to mapping out the full spectrum of PMN antigens. Recent developments suggest exostosin 1 (EXT1), EXT2, NELL-1, and contactin 1 (CNTN1) are associated with MN. Genetic factors and other mechanisms are in place to regulate these factors and may contribute to MN pathogenesis. This review will discuss recent developments over the past 5 years.

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Proteomics of human glomerulonephritis by laser microdissection and liquid chromatography‐tandem mass spectrometry

Cited by 25 publications

References 23 publications

Renal deposition and clearance of recombinant poly‐IgA complexes in a model of IgA nephropathy

Renal deposition and clearance of recombinant poly‐IgA complexes in a model of IgA nephropathy

Proteomic Analysis of Glomerular Proteins in Primary and Bucillamine-induced Membranous Nephropathy

Mechanisms of Primary Membranous Nephropathy

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