Dataset Information

Murine membranous nephropathy: immunization with ?3(IV) collagen fragment induces subepithelial immune complexes and Fc?R-independent nephrotic syndrome.

ABSTRACT: Membranous nephropathy (MN) is a leading cause of nephrotic syndrome in adults and a significant cause of end-stage renal disease, yet current therapies are nonspecific, toxic, and often ineffective. The development of novel targeted therapies requires a detailed understanding of the pathogenic mechanisms, but progress is hampered by the lack of a robust mouse model of disease. We report that DBA/1 mice as well as congenic Fc?RIII(-/-) and FcR?(-/-) mice immunized with a fragment of ?3(IV) collagen developed massive albuminuria and nephrotic syndrome, because of subepithelial deposits of mouse IgG and C3 with corresponding basement membrane reaction and podocyte foot process effacement. The clinical presentation and histopathologic findings were characteristic of MN. Although immunized mice produced genuine anti-?3NC1 autoantibodies that bound to kidney and lung basement membranes, neither crescentic glomerulonephritis nor alveolitis ensued, likely because of the predominance of mouse IgG1 over IgG2a and IgG2b autoantibodies. The ablation of activating IgG Fc receptors did not ameliorate injury, implicating subepithelial deposition of immune complexes and consequent complement activation as a major effector pathway. We have thus established an active model of murine MN. This model, leveraged by the availability of genetically engineered mice and mouse-specific reagents, will be instrumental in studying the pathogenesis of MN and evaluating the efficacy of novel experimental therapies.

SUBMITTER: Zhang JJ

PROVIDER: S-EPMC3311769 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Murine membranous nephropathy: immunization with α3(IV) collagen fragment induces subepithelial immune complexes and FcγR-independent nephrotic syndrome.

Zhang Jun-Jun JJ Malekpour Mahdi M Luo Wentian W Ge Linna L Olaru Florina F Wang Xu-Ping XP Bah Maimouna M Sado Yoshikazu Y Heidet Laurence L Kleinau Sandra S Fogo Agnes B AB Borza Dorin-Bogdan DB

Journal of immunology (Baltimore, Md. : 1950) 20120227 7

Membranous nephropathy (MN) is a leading cause of nephrotic syndrome in adults and a significant cause of end-stage renal disease, yet current therapies are nonspecific, toxic, and often ineffective. The development of novel targeted therapies requires a detailed understanding of the pathogenic mechanisms, but progress is hampered by the lack of a robust mouse model of disease. We report that DBA/1 mice as well as congenic FcγRIII(-/-) and FcRγ(-/-) mice immunized with a fragment of α3(IV) colla ...[more]

PMID: 22371398

Similar Datasets

Project description:BackgroundThe outcome of patients with primary membranous nephropathy (pMN) who present with nephrotic syndrome (NS) is variable and difficult to predict. The goal of this study was to develop a nomogram to predict the risk of progression for specific individuals.MethodsThis retrospective study involved biopsy-proven patients with pMN and NS treated between January 2012 and June 2018. The primary outcome of our investigation was progression, defined as a reduction of estimated glomerular filtration rate (eGFR) that was equal to or over 20% compared with baseline at the end of follow-up or the onset of end-stage renal disease (ESRD). We used backwards stepwise logistic regression analysis to create a nomogram to predict prognosis. The model was validated internally using bootstrap resampling.ResultsA total of 111 patients were enrolled. After a median follow-up of 40.0 months (range 12-92 months), 18.9% (21/111) patients showed progression. Backwards stepwise selection using the Akaike information criterion (AIC) identified the following four variables as independent risk factors for progression, which were all used in the nomogram: age ≥ 65 years [odds ratio (OR) 7.004; 95% confidence interval (CI) 1.783-27.505; p = 0.005], Ln (sPLA2R-Ab) (OR 2.150; 95% CI 1.293-3.577; p = 0.003), Ln (proteinuria) (OR 5.939; 95% CI 1.055-33.436; p = 0.043) and Ln (Uα1m/Cr) (OR 2.808; 95% CI 1.035-7.619; p = 0.043). The discriminative ability and calibration of the nomogram revealed good predictive ability, as indicated by a C-index of 0.888 (95% CI 0.814-0.940) and a bootstrap-corrected C-index of 0.869; calibration curves were also well fitted. A receiver operating characteristic (ROC) curve for the nomogram score revealed significantly better discrimination than each of the three risk factors alone, including Ln (sPLA2R-Ab) [area under the curve (AUC) 0.769], Ln (proteinuria) (AUC 0.653) and Ln (Uα1m) (AUC 0.781) in the prediction of progression (p < 0.05). The optimal cutoff value of the nomogram score was 117.8 with a positive predictive value of 44.4% and a negative predictive value of 98.5%.ConclusionThe nomogram successfully achieved good predictive ability of progression for patients with pMN who present with NS. It can therefore help clinicians to individualize treatment plans and improve the outcome of pMN.

Project description:BackgroundMolecular characterization of nephropathies may facilitate pathophysiologic insight, development of targeted therapeutics, and transcriptome-based disease classification. Although membranous nephropathy (MN) is a common cause of adult-onset nephrotic syndrome, the molecular pathways of kidney damage in MN require further definition.MethodsWe applied a machine-learning framework to predict diagnosis on the basis of gene expression from the microdissected kidney tissue of participants in the Nephrotic Syndrome Study Network (NEPTUNE) cohort. We sought to identify differentially expressed genes between participants with MN versus those of other glomerulonephropathies across the NEPTUNE and European Renal cDNA Bank (ERCB) cohorts, to find MN-specific gene modules in a kidney-specific functional network, and to identify cell-type specificity of MN-specific genes using single-cell sequencing data from reference nephrectomy tissue.ResultsGlomerular gene expression alone accurately separated participants with MN from those with other nephrotic syndrome etiologies. The top predictive classifier genes from NEPTUNE participants were also differentially expressed in the ERCB participants with MN. We identified a signature of 158 genes that are significantly differentially expressed in MN across both cohorts, finding 120 of these in a validation cohort. This signature is enriched in targets of transcription factor NF-κB. Clustering these MN-specific genes in a kidney-specific functional network uncovered modules with functional enrichments, including in ion transport, cell projection morphogenesis, regulation of adhesion, and wounding response. Expression data from reference nephrectomy tissue indicated 43% of these genes are most highly expressed by podocytes.ConclusionsThese results suggest that, relative to other glomerulonephropathies, MN has a distinctive molecular signature that includes upregulation of many podocyte-expressed genes, provides a molecular snapshot of MN, and facilitates insight into MN's underlying pathophysiology.

Dataset Information

Murine membranous nephropathy: immunization with ?3(IV) collagen fragment induces subepithelial immune complexes and Fc?R-independent nephrotic syndrome.

Publications

Murine membranous nephropathy: immunization with α3(IV) collagen fragment induces subepithelial immune complexes and FcγR-independent nephrotic syndrome.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets