Effect of panobinostat, givinostat and ruxolitinib treatment in the anti-GBM mouse model of crescentic glomerulonephritis.
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ABSTRACT:
PROVIDER: PRJNA802133 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR17833500_1.fastq.gz | Fastqsanger.gz | |||
| SRR17833500_2.fastq.gz | Fastqsanger.gz | |||
| SRR17833501_1.fastq.gz | Fastqsanger.gz | |||
| SRR17833501_2.fastq.gz | Fastqsanger.gz | |||
| SRR17833502_1.fastq.gz | Fastqsanger.gz |
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Project description:We demonstrated that in anti-glomerular basement membrane (anti-GBM) glomerulonephritis, crescents derived from clonal amplification of an immature subset of parietal epithelial cells (PECs) and that following treatment of mice with 3 different drugs currently used in haematological stem cell disorders (panobinostat, givinostat and ruxolitinib), only panobinostat exerted beneficial effect. To establish the mechanism of action of panobinostat, we generated single-cell RNA sequencing (scRNAseq) datasets of kidney cells obtained from control mice with anti-GBM glomerulonephritis and of mice treated with the three drugs. The analysis demonstrated that the drugs exerted similar effects on clusters of cells of the immune system, suggesting that all the three drugs elicit similar anti-inflammatory and immunosuppressive properties.
2022-09-24 | GSE195784 | GEO
Project description:We analyzed the impact of the genetic background during experimental passive non-accelerated anti-glomerular basement membrane glomerulonephritis (anti-GBM-GN) (an equivalent to nephrotoxic nephritis) in two different mouse genetic backgrounds (C57BL6/J vs 129S2svPAS/crl). Glomerular extracts have been made at an early time point (e.g day 4 of the induction of the glomerulonephritis). RNA have been extracted following standard procedures.
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Project description:We report the application of unit of bortezomib and panobinostat on LN229 cell , and further explored the mechanism of drugs on GBM cells.
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Project description:BACKGROUND AND OBJECTIVES:Large studies on long-term kidney outcome in patients with anti-glomerular basement membrane (anti-GBM) GN are lacking. This study aimed to identify clinical and histopathologic parameters that predict kidney outcome in these patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS:This retrospective analysis included a total of 123 patients with anti-GBM GN between 1986 and 2015 from six centers worldwide. Their kidney biopsy samples were classified according to the histopathologic classification for ANCA-associated GN. Clinical data such as details of treatment were retrieved from clinical records. The primary outcome parameter was the occurrence of ESRD. Kidney survival was analyzed using the log-rank test and Cox regression analyses. RESULTS:The 5-year kidney survival rate was 34%, with an improved rate observed among patients diagnosed after 2007 (P=0.01). In patients with anti-GBM GN, histopathologic class and kidney survival were associated (P<0.001). Only one of 15 patients with a focal class biopsy sample (?50% normal glomeruli) developed ESRD. Patients with a sclerotic class biopsy sample (?50% globally sclerotic glomeruli) and patients with 100% cellular crescents did not recover from dialysis dependency at presentation. In multivariable analysis, dialysis dependency at presentation (hazard ratio [HR], 3.17; 95% confidence interval [95% CI], 1.59 to 6.32), percentage of normal glomeruli (HR, 0.97; 95% CI, 0.95 to 0.99), and extent of interstitial infiltrate (HR, 2.02; 95% CI, 1.17 to 3.50) were predictors of ESRD during follow-up. CONCLUSIONS:Dialysis dependency, low percentage of normal glomeruli, and large extent of interstitial infiltrate are associated with poor kidney outcome in anti-GBM GN. Kidney outcome has improved during recent years; the success rate doubled after 2007. PODCAST:This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2017_11_21_CJASNPodcast_18_1_v.mp3.
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Project description:The bromodomain inhibitor JQ1 and the histone deacetylase inhibitor panobinostat induce synergistic anticancer effects We analyzed whether JQ1 and panobinostat synergistically modulate gene expression Neuroblastoma SK-N-BE(2) cells were treated with vehicle control, 1 microM JQ1, 10 nM panobinostat, or combination of JQ1 and panobinostat for 6 hours, and subjected to differential gene expression studies with Affymetrix microarrays.
2015-12-31 | E-GEOD-68690 | biostudies-arrayexpress
Project description:BackgroundAnti-glomerular basement membrane (GBM) antibodies are highly specific for Goodpasture's or anti-GBM disease, in which they are generally directed against the non-collagenous (NC1) domain of the alpha 3 chain of type IV collagen(?3(IV)), and less commonly, toward the ? 4(IV) or ? 5(IV) chains, which form a triple helical structure in GBM and alveolar basement membrane (ABM). Alterations in the hexameric structure of the NC1 (?3 (IV)), allows novel epitopes to be exposed and an immune response to develop, with subsequent linear antibody deposition along the GBM, leading to a crescentic glomerulonephritis. Positive anti-GBM antibodies are assumed to be pathogenic and capable of binding GBM in vivo, especially in the context of rapidly progressive glomerulonephritis. We have investigated patients with circulating anti-GBM antibodies, reactive to ?3 (IV) and human GBM by immunoassays and Western blotting respectively, with focal necrotising crescentic glomerulonephritis but no linear GBM antibody deposition on immunohistochemistry. Three out of four were also ANCA positive. Despite not binding native GBM, patients' sera showed linear binding to primate glomeruli by indirect immunofluorescence, in the 2 cases tested. Following treatment, significant improvements in kidney function were found in 3/4 patients.Case presentationWe present four patients with crescentic glomerulonephritis and circulating anti-GBM antibodies, but no glomerular binding.ConclusionsThese novel findings, demonstrate that in some patients anti-GBM antibodies may not bind their own GBM. This has important implications for clinical diagnosis, suggesting that histological confirmation of kidney injury by anti-GBM antibodies should be obtained, as non-binding GBM antibodies may be associated with significant renal recovery.
| S-EPMC6136232 | biostudies-literature
Project description:Myeloid cells and TLR4 play a critical role in acute kidney injury. This study investigated the regulatory role and mechanisms of myeloid TLR4 in experimental anti-glomerular basement membrane (GBM) glomerulonephritis (GN). Anti-GBM GN was induced in tlr4flox/flox and tlr4flox/flox-lysM-cre mice by intravenous injection of the sheep anti-mouse GBM antibody. Compared to control mice, conditional disruption of tlr4 from myeloid cells, largely macrophages (> 85%), suppressed glomerular crescent formation and attenuated progressive renal injury by lowering serum creatinine and 24-h urine protein excretion while improving creatinine clearance. Mechanistically, deletion of myeloid tlr4 markedly inhibited renal infiltration of macrophages and T cells and resulted in a shift of infiltrating macrophages from F4/80+iNOS+ M1 to F4/80+CD206+ M2 phenotype and inhibited the upregulation of renal proinflammatory cytokines IL-1β and MCP-1. Importantly, deletion of myeloid tlr4 suppressed T cell-mediated immune injury by shifting Th1 (CD4+IFNγ+) and Th17 (CD4+IL-17a+) to Treg (CD4+CD25+FoxP3+) immune responses. Transcriptome analysis also revealed that disrupted myeloid TLR4 largely downregulated genes involving immune and cytokine-related pathways. Thus, myeloid TLR4 plays a pivotal role in anti-GBM GN by immunological switching from M1 to M2 and from Th1/Th17 to Treg and targeting myeloid TLR4 may be a novel therapeutic strategy for immune-mediated kidney diseases.
| S-EPMC8558180 | biostudies-literature
Project description:We investigated a glomerulonephritis (GN) model in rats induced by nephrotoxic serum (NTS) which contains antibodies against the glomerular basement membrane (GBM). The anti-GBM GN model in rats is widely used since its biochemical and histopathological characteristics are similar to crescentic nephritis and Goodpasture's disease in humans. Male Wistar Kyoto (WKY) and Sprague Dawley (SD) rats were dosed once with 1, 2.5 and 5 ml/kg nephrotoxic serum (NTS) or 1.5 and 5 ml/kg NTS, respectively. GN and tubular damage were observed histopathologically in all treated rats after 14 days. To obtain insight into molecular processes during GN pathogenesis, mRNA expression was investigated in WKY and SD kidneys. The immunopathological processes during GN are still not fully understood and likely involve both innate and adaptive immunity. In the present study, several hundred mRNAs were found deregulated, which functionally were mostly associated with inflammation and regeneration. The ?-chain of the major histocompatibility complex class II RT1.B (Rt1-Bb) and complement component 6 (C6) were identified as two mRNAs differentially expressed between WKY and SD rat strains which could be related to known different susceptibilities to NTS of different rat strains; both were increased in WKY and decreased in SD rats. Increased Rt1-Bb expression in WKY rats could indicate a stronger and more persistent cellular reaction of the adaptive immune system in this strain, in line with findings indicating adaptive immune reactions during GN. The complement cascade is also known to be essential for GN development, especially terminal cascade products like C6. Two different rat strains (WKY and SD) were dosed with different doses of NTS and after 14 days rats were euthanized and kidneys were removed for RNA extraction and hybridization on Affymetrix microarrays. We sought to analyze the deregulation of gene expression during NTS-induced glomerulonephritis and to compare the effect in the two rat strains.
2015-07-06 | E-GEOD-64265 | biostudies-arrayexpress
Project description:In September 2010, a 75-year-old hepatitis B virus (HBV)-positive man was admitted to our hospital because of fever, persistent cough, general fatigue, and leg edema. The patient was a hepatitis B surface antigen carrier with detectable HBV DNA level. On admission, laboratory examination revealed severe inflammatory signs, decreased serum albumin, and renal insufficiency with proteinuria. The patient had rapidly progressive renal insufficiency without pulmonary involvement over the few days after admission. Renal biopsy showed membranous nephropathy (MN) with crescent formation. Further serological study revealed a high titer of anti-glomerular basement membrane (GBM) antibody, suggestive of anti-GBM glomerulonephritis superimposed on HBV-associated MN. For both preventing HBV reactivation during immunosuppressive therapy and treating HBV-associated MN, the administration of entecavir was immediately initiated, and then treatment with plasma exchange (PE) and intravenous methylprednisolone administration was performed. Both HBV DNA level and an anti-GBM titer became undetectable, and clinical remission of MN was subsequently achieved. This was a rare case of an elderly patient with anti-GBM glomerulonephritis superimposed on HBV-associated MN, who was successfully treated with PE, corticosteroid, and entecavir combination therapy.
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Project description:Single-cell TCR sequencing of T cells from ANCA-associated glomerulonephritis patients and experimental crescentic glomerulonephritis mouse model.
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