MyD88 deficiency in podocytes does not change the outcome in experimental glomerulonephritis.
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ABSTRACT:
PROVIDER: PRJNA922898 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23048689_1.fastq.gz | Fastqsanger.gz | |||
| SRR23048689_2.fastq.gz | Fastqsanger.gz | |||
| SRR23048690_1.fastq.gz | Fastqsanger.gz | |||
| SRR23048690_2.fastq.gz | Fastqsanger.gz | |||
| SRR23048691_1.fastq.gz | Fastqsanger.gz |
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Project description:Podocytes, together with glomerular endothelial cells, form the kidney filtration barrier. Loss of podocyte function leads to proteinuria and end-stage renal disease. Podocytes are damaged by various diseases. How they respond to damage-associated molecular patterns is however incompletely understood. MyD88 is the central adaptor protein downstream of Toll-like receptor (TLR) / interleukin-1 (IL-1) signaling and key to the initiation of inflammatory responses.
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Project description:Proliferative glomerulonephritis is a severe condition often leading to kidney failure. There is a significant lack of effective treatment for these disorders. Here, following the identification of a somatic PIK3CA gain-of-function mutation in podocytes of a patient, we demonstrate using multiple genetically engineered mouse models, single-cell RNA sequencing and spatial transcriptomics the crucial role played by this pathway for proliferative glomerulonephritis development by promoting podocyte proliferation, dedifferentiation and inflammation. Additionally, we show that alpelisib, a PI3Kα inhibitor, improves glomerular lesions and kidney function in different mouse models of proliferative glomerulonephritis and lupus nephritis by targeting podocytes. Surprisingly, we determined that pharmacological inhibition of PI3Kα affects B and T lymphocyte population in lupus nephritis mouse models with decrease in the production of proinflammatory cytokines, autoantibodies and glomerular complement deposition, which are all characteristic features of PI3K delta (PI3Kδ) inhibition, the primary PI3K isoform expressed in lymphocytes. Importantly, PI3Kα inhibition does not impact lymphocyte function under normal conditions. These findings were then confirmed in human lymphocytes isolated from patients with active lupus nephritis. In conclusion, we demonstrate the major role played by PI3Kα in proliferative glomerulonephritis and show that in this condition, alpelisib acts on both podocytes and the immune system.
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Project description:Isthmin-1 is a novel mediator of experimental glomerulonephritis through a pro-apoptotic action in podocytes
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Project description:Glomerulonephritis is one of the major complications and causes of death in systemic lupus erythematosus (SLE). Podocytes can be injured in many forms of glomerular disease, characteristic changes are actin cytoskeleton reorganization of involved foot process. ACTN4, encodes α-actinin-4, an actin-binding and crosslinking protein localized to podocytes in renal glomerulus. Abnormal expression of α-actinin-4 in mice leads to proteinuria and podocyte damage. DZ2002, a reversible S-adenosyl-L-homocysteine hydrolase (SAHH) inhibitor with immunosuppressive properties and potent therapeutic activity against various autoimmune diseases in mice. Here, we found that DZ2002 could significantly ameliorate nephritis of lupus-prone mice. Our results showed that DZ2002 decreased the accumulation of α-actinin-4, inhibited expression of integrin-linked kinase and downstream phosphorylation of β1-integrin.
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Project description:Parietal epithelial cells (PECs) are crucially involved in the pathogenesis of rapidly progressive glomerulonephritis (RPGN) as well as in focal and segmental glomerulosclerosis (FSGS). In this study, transgenic mouse lines were used to isolate pure, genetically tagged primary cultures of PECs or podocytes using FACsorting. By this approach, the morphology of primary glomerular epithelial cells in culture could be resolved: Primary podocytes formed either large cells with intracytoplasmatic extensions or smaller spindle shaped cells, depending on specific culture conditions. Primary PECs were small and exhibited a spindle-shaped or polygonal morphology. In the very early phases of primary culture, rapid changes in gene expression (e.g. of WT-1 and Pax-2) were observed. However, after prolonged culture primary PECs and podocytes still segregated clearly in a transcriptome analysis - demonstrating that the origin of primary cell cultures is important. Of the classical markers, synaptopodin and podoplanin expression were differentially regulated the most in primary PEC and podocyte cultures. However, no expression of any endogenous gene allowed to differentiate between the two cell types in culture. Finally, we show that the transcription factor WT1 is also expressed by PECs. In summary, genetic tagging of PECs and podocytes is a novel and necessary tool to derive pure primary cultures with proven origin. These cultures will be a powerful tool for the emerging field of parietal epithelial cell biology. Total RNA for genechip analysis was derived from: 1) Primary parietal cells isolated by FACS sorting of glomeruli cultivated in 1a) RPMI media 1b) EGM-MV media 2) Primary podocyte cells isolated by FACS sorting of glomeruli cultivated in 2a) RPMI media 2b) EGM-MV media
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Project description:Annexin A1 exerts renoprotective effects in experimental crescentic glomerulonephritis
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Project description:Purpose: Next-generation sequencing (NGS) was used to define the transcriptome of native mouse podocytes and non-podocytes glomerular cells as part of a project aiming to define the molecular fingerprint of mouse podocytes. Method: Glomeruli from 29 Gt(ROSA)26Sortm4(ACTB-tdTomato,-EGFP)Luo/J x hNPHS2Cre mice at the age of 10 weeks were purified and a single cell solution was prepared to seperate GFP-expressing (podocytes) and GFP-negative (non-podocytes glomerular cells) cells by FACS sorting. RNA was extracted and prepared for further analysis using directional, polyA+ library preparation. An Illumina HiSeq2500 was used for a paired-end sequencing of 100 cycles . Salmon and Sleuth were used for downstream analysis. Results: A total of 100 Million reads each from podocytes and non-podocytes glomerular cells could be used for further analysis.
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Project description:Anti neutrophil cytoplasmic antibody (ANCA) associated vasculitis is the most frequent cause of crescentic glomerulonephritis. Histopathologic features and clinical course of the disease are diverse and judgment of disease activity is often limited due to the lack of reliable activity markers. In order to define potentially new molecular or cellular markers in the kidney which may predict clinical outcome, we performed microarray analyses of renal biopsies from patients with ANCA-associated crescentic glomerulonephritis. We correlated expression profiles with clinical data from our prospective study of patients with renal ANCA disease. The CC chemokine ligand 18 (CCL18) was one of the most up-regulated proteins in kidneys of patients with ANCA-associated crescentic glomerulonephritis. CCL18 producing cells in the kidneys were identified as CD68 and CD209 positive myeloid dendritic cells. The density of CCL18 positive cells correlated with the severity of acute tubular injury and with the impairment of renal function. CCL18 protein levels were elevated in serum samples of patients with renal ANCA disease when compared with patients with non- ANCA-associated crescentic glomerulonephritis. Persistence of high CCL18 serum levels correlated with impairment of renal function and the risk of relapsing disease. Therefore, CCL18 might serve as a marker for persistent disease activity and renal relapses in ANCA-associated vasculitis.
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Project description:Innate lymphoid cells (ILCs) that express NK cell receptors (NCRs) and the transcription factor T-bet populate non-lymphoid tissues and are crucial in immune responses against viral infections and malignancies. Recent studies highlighted the heterogeneity of this ILC population and extended their functional spectrum to include important roles in tissue homeostasis and autoimmunity. Here, we provide detailed profiling of NCR+T-bet+ ILC populations in the murine kidney, identifying conventional NK (cNK) cells and type 1 ILCs (ILC1s) as the two major subsets. Induction of renal inflammation in a mouse model of glomerulonephritis did not substantially influence abundance or phenotype of cNK cells or ILC1s in the kidney. For functional analyses in this model, widely used depletion strategies for total NCR+ ILCs (αNK1.1 antibody application) and cNK cells (α-asGM1 serum application) were unreliable tools, since they were accompanied by significant off-target depletion of kidney NKT cells and CD8+ T cells, respectively. However, neither depletion of cNK cells and ILC1s in NKT cell-deficient mice, nor specific genetic deletion of cNK cells in Ncr1Cre/wt x Eomesfl/fl mice altered the clinical course of experimental glomerulonephritis. In summary, we show here that cNK cells and ILC1s are dispensable for initiation and progression of immune-mediated glomerular disease and advise caution in the use of standard antibody depletion methods to study NCR+ ILC function in mouse models.
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