Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Shared molecular targets in the glomerular transcriptome from patients with nephrotic syndrome and ANCA-associated vasculitis

ABSTRACT: Glomerular transcriptome from human kidney biopsies in Neptune and ERCB. A subset of samples profiled in this analysis were also profiled in Series GSE68127, and in GSE104066. Corresponding tubulointerstitial transcriptome data is submitted under GEO ID: GSE108113. RNA from the glomerular compartment was extracted and processed for hybridization on Affymetrix ST 2.1 microarrays, annotated using Human Entrez Gene ID custom CDF version 19. This dataset is part of the TransQST collection.

ORGANISM(S): Homo sapiens

SUBMITTER: Sean Eddy

PROVIDER: E-GEOD-108109 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Metabolic pathways and immunometabolism in rare kidney diseases.

Grayson Peter C PC Eddy Sean S Taroni Jaclyn N JN Lightfoot Yaíma L YL Mariani Laura L Parikh Hemang H Lindenmeyer Maja T MT Ju Wenjun W Greene Casey S CS Godfrey Brad B Cohen Clemens D CD Krischer Jeffrey J Kretzler Matthias M Merkel Peter A PA

Annals of the rheumatic diseases 20180503 8

<h4>Objectives</h4>To characterise renal tissue metabolic pathway gene expression in different forms of glomerulonephritis.<h4>Methods</h4>Patients with nephrotic syndrome (NS), antineutrophil cytoplasmic antibody-associated vasculitis (AAV), systemic lupus erythematosus (SLE) and healthy living donors (LD) were studied. Clinically indicated renal biopsies were obtained at time of diagnosis and microdissected into glomerular and tubulointerstitial compartments. Microarray-derived differential ge ...[more]

PMID: 29724730

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Project description:Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are severe inflammatory disorders that often lead to rapid and irreversible organ failure. Rapid progressive glomerulonephritis (RPGN) is a particularly frequent renal manifestation and often leads to extensive glomerular scarring and interstitial fibrosis, resulting in chronic kidney disease and end stage renal failure. Current management options of AAV and its sequelae are limited and common therapies have serious side effects that impair quality of life. A better understanding of the deleterious scarring process of AAV may help to identify novel mechanisms and potential targets for therapy. However, robust murine models of scarring RPGN are still lacking. Here, we present a novel murine model of severe RPGN that recapitulates both acute injury and the subsequent glomerular and interstitial scarring that is based on combined administration of antibodies against the glomerular basement membrane (GBM) and myeloperoxidase (MPO), and bacterial lipopolysaccharides (LPS). Renal injury presented with severe hematuria, glomerular necrosis and crescent formation at 12 days, and consequent glomerular scarring 29 days after initial treatment. We observed increased expression of matrisomal components such as collagens, fibronectin, tenascin-C, in accordance with human AAV as deduced from analysis of gene expression microarray data and tissue staining. Moreover, we observed tissue infiltration by neutrophils, macrophages, T cells and myofibroblasts upon injury. Inhibition of CXCR4 using AMD3100 led to histological and molecular changes in injury with reduced chemokine expression and lower immune cells activation. Using mass-spectrometric proteome analysis, we provide a comprehensive overview of molecular and cellular changes in our AAV model. Altogether, we demonstrate a novel RPGN model that enables the study of matrisomal changes both in disease and upon intervention, as exemplified via CXCR4 inhibition, which could prove to be a viable pharmacological tool and provide matrix as novel targeting opportunity.

Project description:Antineutrophil cytoplasm antibody (ANCA)-associated vasculitides are small-vessel vasculitides that include granulomatosis with polyangiitis (formerly Wegener's granulomatosis), microscopic polyangiitis, and eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome). Renal-limited ANCA-associated vasculitides can be considered the fourth entity. Despite their rarity and still unknown cause(s), research pertaining to ANCA-associated vasculitides has been very active over the past decades. The pathogenic role of antimyeloperoxidase ANCA (MPO-ANCA) has been supported using several animal models, but that of antiproteinase 3 ANCA (PR3-ANCA) has not been as strongly demonstrated. Moreover, some MPO-ANCA subsets, which are directed against a few specific MPO epitopes, have recently been found to be better associated with disease activity, but a different method than the one presently used in routine detection is required to detect them. B cells possibly play a major role in the pathogenesis because they produce ANCAs, as well as neutrophil abnormalities and imbalances in different T-cell subtypes [T helper (Th)1, Th2, Th17, regulatory cluster of differentiation (CD)4+ CD25+ forkhead box P3 (FoxP3)+ T cells] and/or cytokine-chemokine networks. The alternative complement pathway is also involved, and its blockade has been shown to prevent renal disease in an MPO-ANCA murine model. Other recent studies suggested strongest genetic associations by ANCA type rather than by clinical diagnosis. The induction treatment for severe granulomatosis with polyangiitis and microscopic polyangiitis is relatively well codified but does not (yet) really differ by precise diagnosis or ANCA type. It comprises glucocorticoids combined with another immunosuppressant, cyclophosphamide or rituximab. The choice between the two immunosuppressants must consider the comorbidities, past exposure to cyclophosphamide for relapsers, plans for pregnancy, and also the cost of rituximab. Once remission is achieved, maintenance strategy following cyclophosphamide-based induction relies on less toxic agents such as azathioprine or methotrexate. The optimal maintenance strategy following rituximab-based induction therapy remains to be determined. Preliminary results on rituximab for maintenance therapy appear promising. Efforts are still under way to determine the optimal duration of maintenance therapy, ideally tailored according to the characteristics of each patient and the previous treatment received.

Dataset Information

Shared molecular targets in the glomerular transcriptome from patients with nephrotic syndrome and ANCA-associated vasculitis

Publications

Metabolic pathways and immunometabolism in rare kidney diseases.

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