The Molecular Phenotype of Lupus Nephritis Histological Lesions
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE127797 | GEO | 2019/10/29
REPOSITORIES: GEO
Similar Datasets
Project description:Nephritis (LN) is a serious manifestation of SLE. Therapeutic studies in mouse LN models do not always predict outcomes of human therapeutic trials, raising concerns about the human relevance of these models. In this study we used an unbiased transcriptional network approach to define similarities and differences between three lupus models and human LN. Affymetrix-based expression profiles were analyzed using Genomatix Bibliosphere software and transcriptional networks were compared using the Tool for Approximate LargE graph matching (TALE). The 20 network hubs (nodes) shared between all three models and human LN reflect key pathologic processes, namely immune cell infiltration/activation, macrophage/dendritic cell activation, endothelial cell activation/injury and tissue remodeling/fibrosis. Each model also shares unique features with human LN. Pathway analysis of the TALE nodes highlighted macrophage/DC activation as a cross-species shared feature. To distinguish which genes and activation pathways might derive from mononuclear phagocytes in the human kidneys the gene expression profile of isolated NZB/W renal mononuclear cells was compared with human LN kidney profiles. Network analysis of the shared signature highlighted NFkappaB1 and PPARgamma as major hubs in the tubulointerstitial and glomerular networks respectively. Key nodes in the renal macrophage inflammatory response form the basis for further mechanistic and therapeutic studies. We used microarrays to analyze the transcriptome of microdissected renal biopsies from patients with lupus nephritis (LN) RNA from glomeruli and tubulointerstitial compartments was extracted and processed for hybridization on Affymetrix microarrays.
2012-06-27 | E-GEOD-32591 | biostudies-arrayexpress
Project description:Nephritis (LN) is a serious manifestation of SLE. Therapeutic studies in mouse LN models do not always predict outcomes of human therapeutic trials, raising concerns about the human relevance of these models. In this study we used an unbiased transcriptional network approach to define similarities and differences between three lupus models and human LN. Affymetrix-based expression profiles were analyzed using Genomatix Bibliosphere software and transcriptional networks were compared using the Tool for Approximate LargE graph matching (TALE). The 20 network hubs (nodes) shared between all three models and human LN reflect key pathologic processes, namely immune cell infiltration/activation, macrophage/dendritic cell activation, endothelial cell activation/injury and tissue remodeling/fibrosis. Each model also shares unique features with human LN. Pathway analysis of the TALE nodes highlighted macrophage/DC activation as a cross-species shared feature. To distinguish which genes and activation pathways might derive from mononuclear phagocytes in the human kidneys the gene expression profile of isolated NZB/W renal mononuclear cells was compared with human LN kidney profiles. Network analysis of the shared signature highlighted NFkappaB1 and PPARgamma as major hubs in the tubulointerstitial and glomerular networks respectively. Key nodes in the renal macrophage inflammatory response form the basis for further mechanistic and therapeutic studies. We used microarrays to analyze the renal transcriptome of three different lupus mouse models, at early stage of lupus and during lupus nephritis. RNA from whole kidneys was extracted and processed for hybridization on Affymetrix microarrays.
2012-08-01 | E-GEOD-32583 | biostudies-arrayexpress
Project description:The immune pathways that define treatment response and non-response in lupus nephritis (LN) are unknown. To characterize these intra-renal pathways, transcriptomic analysis of protocol kidney biopsies was done. Kidney biopsies were done at flare (Bx1) and after treatment (Bx2) in 58 LN patients and healthy controls (HC). Glomeruli and tubulointerstitium (TI) were isolated using laser microdissection. RNA was extracted and analyzed by nanostring. Transcript expression from clinical complete (CR), partial (PR) and non-responders (NR) were compared at Bx1 and Bx2 and to HC. Top transcripts that differentiate CR from NR were identified. Confocal microscopy and urine ELISA was done to evaluate the protein expression of top transcripts. At Bx1 cluster analysis determined that glomerular integrin, neutrophil, and chemokine/cytokine, and TI chemokine, T cell and leukocyte adhesion genes differentiated NR from CR. At Bx2, glomerular monocyte, extracellular matrix, and interferon, and TI interferon, complement, and T cell transcripts differentiated NR from CR. Protein analysis recapitulated top transcript findings. Urine C5a and FN1 differentiated NR from CR after treatment. Transcript analysis of serial kidney biopsies taken during the treatment of LN demonstrated how gene expression in the kidney changes with clinically successful and unsuccessful therapy. These insights into the molecular landscape of response and non-response may help better align LN management with the pathogenesis of kidney injury.
2022-07-15 | GSE200306 | GEO
Project description:Nephritis (LN) is a serious manifestation of SLE. Therapeutic studies in mouse LN models do not always predict outcomes of human therapeutic trials, raising concerns about the human relevance of these models. In this study we used an unbiased transcriptional network approach to define similarities and differences between three lupus models and human LN. Affymetrix-based expression profiles were analyzed using Genomatix Bibliosphere software and transcriptional networks were compared using the Tool for Approximate LargE graph matching (TALE). The 20 network hubs (nodes) shared between all three models and human LN reflect key pathologic processes, namely immune cell infiltration/activation, macrophage/dendritic cell activation, endothelial cell activation/injury and tissue remodeling/fibrosis. Each model also shares unique features with human LN. Pathway analysis of the TALE nodes highlighted macrophage/DC activation as a cross-species shared feature. To distinguish which genes and activation pathways might derive from mononuclear phagocytes in the human kidneys the gene expression profile of isolated NZB/W renal mononuclear cells was compared with human LN kidney profiles. Network analysis of the shared signature highlighted NFkappaB1 and PPARgamma as major hubs in the tubulointerstitial and glomerular networks respectively. Key nodes in the renal macrophage inflammatory response form the basis for further mechanistic and therapeutic studies. We used microarrays to analyze the transcriptome of microdissected renal biopsies from patients with lupus nephritis (LN)
2012-06-28 | GSE32591 | GEO
Project description:We aim to identify profiling of circRNAs in renal biopsies from lupus nephritis (LN) patients. In this study, seven frozen renal biopsies from patients with LN class IV were used for circRNA profiling by second generation of RNA sequencing. Three kidney tissue 5 cm far from renal tumors were used as normal control .
2020-12-16 | GSE108340 | GEO
Project description:Nephritis (LN) is a serious manifestation of SLE. Therapeutic studies in mouse LN models do not always predict outcomes of human therapeutic trials, raising concerns about the human relevance of these models. In this study we used an unbiased transcriptional network approach to define similarities and differences between three lupus models and human LN. Affymetrix-based expression profiles were analyzed using Genomatix Bibliosphere software and transcriptional networks were compared using the Tool for Approximate LargE graph matching (TALE). The 20 network hubs (nodes) shared between all three models and human LN reflect key pathologic processes, namely immune cell infiltration/activation, macrophage/dendritic cell activation, endothelial cell activation/injury and tissue remodeling/fibrosis. Each model also shares unique features with human LN. Pathway analysis of the TALE nodes highlighted macrophage/DC activation as a cross-species shared feature. To distinguish which genes and activation pathways might derive from mononuclear phagocytes in the human kidneys the gene expression profile of isolated NZB/W renal mononuclear cells was compared with human LN kidney profiles. Network analysis of the shared signature highlighted NFkappaB1 and PPARgamma as major hubs in the tubulointerstitial and glomerular networks respectively. Key nodes in the renal macrophage inflammatory response form the basis for further mechanistic and therapeutic studies. We used microarrays to analyze the renal transcriptome of three different lupus mouse models, at early stage of lupus and during lupus nephritis.
2012-08-02 | GSE32583 | GEO
Project description:Both a lack of biomarkers and relatively ineffective treatments constitute impediments to management of lupus nephritis (LN). Here we used gene expression microarrays to contrast the transcriptomic profiles of active SLE patients with and without LN to identify potential biomarkers for LN. RNA isolated from whole peripheral blood of active SLE patients was used for transcriptomic profiling and the data analyzed by linear modeling, with corrections for multiple testing. Results were validated in a second cohort of SLE patients, using NanoString technology. The majority of genes demonstrating altered mRNA abundance between patients with and without LN were neutrophil-related. Findings in the validation cohort confirmed this observation and showed that the levels of gene expression in renal remission were similar to active patients without LN. In secondary analyses, gene expression correlated with disease activity, hematuria and proteinuria, but not renal biopsy changes. As expression levels of the individual genes correlated strongly with each other, a composite neutrophil score was generated by summing all levels before examining additional correlations. There was a modest correlation between the neutrophil score and the blood neutrophil count, which was largely driven by the dose of steroids and not the proportion of low density and/or activated neutrophils. Analysis of longitudinal data revealed no correlation between baseline neutrophil score or changes over the first year of follow-up with subsequent renal flare or treatment outcomes, respectively. The findings argue that although the neutrophil score is associated with LN, its clinical utility as a biomarker may be limited.
2018-02-28 | GSE99967 | GEO
Project description:We aimed to identify miRNA biomarkers of renal injury in kidney biopsies from patients with lupus nephritis. MiRNA profiles of 8 patients were analyzed for correlation with various clinical features including Progression, Activity, Chronicity, and Time to Kidney Failure. MicroRNAs (miRs) are promising biomarkers and are involved in pathogenesis of kidney diseases. We aimed to identify miR biomarkers of renal injury in kidney biopsies from patients with lupus nephritis and study their potential role in renal fibrosis. miR-150 was significantly increased in kidneys with high chronicity compared to low chronicity and it correlated positively with chronicity index scores and renal collagen I expression. In kidneys with high chronicity, miR-150 was found predominantly in proximal tubular cells (PTCs) and was moderately expressed in podocytes and to lesser degree in mesangial cells (MCs). We hypothesized that miR-150 increases fibrosis by downregulating a negative regulator of profibrotic proteins. Suppressor of cytokine signaling1 (SOCS1) is a predicted target of miR-150 and has shown antifibrotic role. After confirming that SOCS1 is a direct target of miR-150, we showed that transfection of a miR-150 analog downregulated SOCS1 protein and upregulated the profibrotic proteins fibronectin, collagen I, collagen III, and TGF-β1 in both primary normal human renal PTCs and MCs. A similar effect was seen when using a SOCS1 siRNA to confirm that the effect of miR-150 on profibrotic proteins is mediated through SOCS1. Stimulation with TGF-β1 induced miR-150 increase in PTCs and human podocytes but not MCs. These results suggest that miR-150 might be a useful quantitative renal biomarker of kidney injury in lupus nephritis and that miR-150, which might be partially induced by TGF-β1, plays an important role in renal fibrosis by increasing profibrotic molecules through downregulation of SOCS1. FFPE kidney specimens (n=25) including baseline and repeated needle renal biopsies were from 14 patients with LN enrolled in IRB-approved protocols at the NIDDK between 1976 and 1999. The specimens were divided in two groups based on histological chronicity index (CI). CI ≥ 4 were categorized as having high degree of chronicity of chronic kidney injury. 18 kidneys from 8 patients including high CI (n=9) and low CI (n=9) were used for miR profiling by Affymetrix microRNA microarrays.
2012-12-01 | E-GEOD-42648 | biostudies-arrayexpress
Project description:Immune aggregates organized as tertiary lymphoid structures (TLS) are observed within kidneys of systemic lupus erythematosus (SLE) patients with lupus nephritis (LN). We characterized renal TLS in lupus-prone (NZBxNZW) F1 mice with respect to cell composition and vessel formation. Ribonucleic acid (RNA) sequencing was performed on transcriptomes isolated from Lymph nodes (LyN), macro-dissected TLS from kidneys, and total kidneys of mice at different disease stages by using Ion Torrent Personal Genome Machine (Ion PGM) and RNAseq from Illumina. Formation of TLS was found in anti-dsDNA antibody positive mice and the structures were organized as interconnected large networks with distinct T and B cell zones with adjacent dendritic cells, macrophages, plasma cells, high endothelial venules, supporting follicular dendritic cells network, and functional germinal centers. Comparison of gene profiles of whole kidney, renal TLS and LyN revealed a similar gene signature of TLS and LyN. The upregulated genes within the kidneys of lupus-prone mice during the development of LN reflected the TLS formation, while the downregulated genes were involved in metabolic processes of the kidney cells. A comparison with human LN gene expression revealed similar upregulated genes as observed during the development of murine LN and TLS. We conclude that kidney TLS have a similar cell composition, structure and gene signature as LyN, and therefore may function as a kidney specific type of LyN.
2020-07-30 | GSE155405 | GEO
Project description:Lupus nephritis (LN) often results in progressive renal dysfunction. The inactive Rhomboid 2 (iRhom2) is a newly identified key regulator of A disintegrin and metalloprotease 17 (ADAM17), whose substrates, such as TNF-α and heparin-binding EGF (HB-EGF), have been implicated in the pathogenesis of chronic kidney disease. Here we demonstrate that deficiency of iRhom2 protects the lupus-prone Fcgr2b-/- mice from developing severe kidney damage without altering anti-double stranded (ds) DNA Ab production, by simultaneously blocking the HB-EGF/EGFR and the TNF-α signaling in the kidney tissues. Unbiased transcriptome profiling of kidneys and kidney macrophages revealed that TNF-α and HB-EGF/EGFR signaling pathways are highly upregulated in Fcgr2b-/- mice; alterations that were diminished in the absence of iRhom2. Pharmacological blockade of either TNF-α or EGFR signaling protected Fcgr2b-/- mice from severe renal damage. Finally, kidneys from LN patients showed increased iRhom2 and HB-EGF expression, with interstitial HB-EGF expression significantly associated with chronicity indices. Our data suggest that activation of iRhom2/ADAM17-dependent TNF-α and EGFR signaling plays a crucial role in mediating irreversible kidney damage in LN, thereby uncovering a novel target for selective and simultaneous dual inhibition of two major pathological pathways in the effector arm of the disease.
2019-01-01 | GSE107705 | GEO