Immune landscape of PBMC based on single-cell rna sequancing in End Stage Renal Disease
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE233315 | GEO | 2023/10/31
REPOSITORIES: GEO
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Project description:PBMCs were isolated from normal CKD patient, end-stage renal disease patients without HF (ESRD), ESRD patients with HFpEF, and heart failure with reduced ejection fraction (HFrEF). The difference expression genes (DEGs) in PBMCs among different groups were compared using microarray.
2023-12-30 | E-MTAB-13612 | biostudies-arrayexpress
Project description:Kidney stones (KS) are very common, excruciating, and are associated with tremendous healthcare cost, chronic kidney disease (CKD), and end stage renal disease (ESRD). Most KS are composed of calcium oxalate and very small increases in urine oxalate concentration increase the risk for stone formation. Besides its critical role in the pathogenesis of KS, emerging data suggest that disturbed oxalate homeostasis (hyperoxaluria and/or hyperoxalemia) contributes to CKD progression, CKD - and ESRD-associated cardiovascular diseases, progression of cyst growth in autosomal dominant polycystic kidney disease (ADPKD), and delayed graft function & poor renal allograft survival. This emphasizes the urgent need for plasma and urinary oxalate lowering therapies, and enhancing the bowel’s ability to secrete oxalate may effectively do so. We previously identified Oxalobacter formigenes (O. formigenes)-derived factors secreted in its culture conditioned medium (CM) which stimulated oxalate transport by human intestinal Caco2-BBE (C2) cells and reduced urinary oxalate excretion in hyperoxaluric mice by enhancing colonic oxalate secretion. Given their remarkable therapeutic potential, we now identified several proteins belonging to Sel1-like family as the major O. formigenes-derived secreted factors, and we determined the crystal structures for six proteins to better understand their function. Importantly, Sel1-14-derived small peptides P8 & P9 were identified as the major factors, with P8+9 closely recapitulate the CM’s effects, including acting through the oxalate transporters SLC26A2 & SLC26A6 and PKA activation. P8+9 also stimulate oxalate transport by human ileal and colonic organoids, confirming that these peptides work in human tissues. Collectively, the identification of these small peptides provide a great opportunity for developing a peptide-based novel therapeutic for hyperoxalemia, hyperoxaluria, and related disorders, impacting the outcomes of patients suffering from KS, primary hyperoxaluria, CKD, ADPKD, ESRD, and renal transplant recipients.
2023-07-24 | PXD024992 | Pride
Project description:Cardiovascular disease is the major cause of morbidity and death in patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD). Patients with CKD and ESRD are at high risk for myocardial dysfunction, ischemia and heart failure. The mechanisms linking impaired renal function and increased risk for cardiovascular diseases, however, remain elusive. In addition, conventional therapeutics proven effective in reducing cardiovascular events in general population fail to provide similar benefits in uremic patients. There is a clear need to identify novel mediators of cardiovascular complications in uremic patients to provide insights into the pathogenesis, to tailor clinical care based on cardiovascular risks, and to develop new therapeutic strategies. It has become increasingly clear that the transcription of the eukaryotic genome is far more pervasive and complex than previously appreciated. While the expression of messenger RNAs (mRNAs) and microRNAs (miRNAs) account for only ~1% of all transcribed species, up to 90% of the mammalian genome is transcribed as long non-coding RNAs (lncRNAs), a heterogeneous group of non-coding transcripts longer than 200 nucleotides. LncRNAs have been shown to be functional and involved in specific physiological and pathological processes through epigenetic, transcriptional and post-transcriptional mechanisms. While the roles of lncRNAs in human diseases including cancer and neurodegenerative disorders are beginning to emerge, it remains unclear how lncRNA regulation contributes to cardiovascular complications in patients with renal dysfunction. In this proposal, we seek to apply next-generation sequencing technology to investigate circulating (plasma) lncRNA expression in control subjects and in patients with CKD and ESRD. We will test the hypothesis that circulating lncRNA expression signature can reflect the underlying kidney disease states in patients with CKD and ESRD. In addition, we will determine if circulating lncRNA expression signature could be a sensitive and specific biomarker to predict adverse cardiovascular events in patients with ESRD.
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Project description:Chronic kidney disease (CKD) can induce AoSMCs premature senescence and phenotypic switching, which ultimately promotes AS progression and plaque vulnerability. However, the underlying mechanisms are still unknown. To identify the underlying mechanisms of AoSMCs senescence and phenotype switching in CKD. We performed integrated microarray analysis of AoSMCs from normal-diet fed ApoE-/- (ND) mice, high fat-fed ApoE-/- (AS) mice and CKD ApoE-/- (accelerated atherosclerosis mouse model, AAS) mice.
2019-08-10 | GSE135626 | GEO
Project description:Purpose: End-stage renal disease (ESRD) is a condition that is characterized by the loss of kidney function. ESRD patients suffer from various endothelial dysfunctions, inflammation, and immune system defects. Lysine malonylation (Kmal) is a recently discovered post-translational modification (PTM). Although Kmal has the ability to regulate a wide range of biological processes in various organisms, its specific role in ESRD is limited. Experimental design: In this study, the affinity enrichment and liquid chromatography-tandem mass spectrometry (LC-MS/MS) techniques have been used to create the first global proteome and malonyl proteome (malonylome) profiles of peripheral blood mononuclear cells (PBMCs) from twenty patients with ESRD and eighty-one controls. Results: On analysis, 793 differentially expressed proteins (DEPs) and 12 differentially malonylated proteins (DMPs) with 16 Kmal sites were identified. The Rap1 signaling pathway and platelet activation pathway were found to be important in the development of chronic kidney disease (CKD), as were DMPs TLN1 and ACTB, as well as one malonylated site. One conserved Kmal motif was also discovered. Conclusion: These findings provided the first report on the Kmal profile in ESRD, which could be useful in understanding the potential role of lysine malonylation modification in the development of ESRD.
2023-10-24 | PXD035147 | Pride
Project description:End-stage renal disease (ESRD) is the final stage of chronic kidney disease, which is increasingly prevalent worldwide and is associated with the progression of cardiovascular disease (CVD). Despite accumulating evidence that monocytes/macrophages play a pivotal role in the pathogenesis of CVDs in ESRD patients, the current knowledge of transcriptomic signatures of monocytes or macrophages in ESRD patients is very lacking. Therefore, we investigated the transcriptome profiling of monocyte separated from patients with ESRD and HC. To explore the changes of gene expression in ESRD patient-derived monocytes, compared to monocytes from healthy controls, microarray were performed.
2020-07-30 | GSE155326 | GEO
Project description:Background Chronic kidney disease (CKD) is the progressive loss of renal function. Although advances have been made in understanding the progression of CKD, key molecular events in complex pathophysiological mechanisms that mark each stage of renal failure remain largely unknown. Changes in plasma protein profiles in different disease stages are important for identification of early diagnostic markers and potential therapeutic targets. The goal of this study was to determine the molecular profile of each CKD stage (from 1 to 5), aiming to specifically point out markedly expressed or downregulated proteins. Methods We performed a cross-sectional shotgun-proteomic study of plasma proteome across CKD stages and compared them to healthy controls. After sample pooling and heparin-column purification we analysed proteomes from healthy to CKD stage 1 through 5 participants’ plasma by liquid-chromatography/mass-spectrometry. Results We identified 298 proteins in all study groups, as well as several outliers. Our results indicate that key events, that may later affect the course of disease progression and the overall pathophysiological background, are most pronounced in CKD stage 2, with an emphasis on inflammation, lipoprotein metabolism, angiogenesis and tissue regeneration. Conclusions Our data is consistent with multiple previous studies in CKD research, but also uncovers previously unknown CKD mediators and brings forth several novel potential protein-candidates which might have a significant impact on the development of diagnostic and therapeutic strategies for CKD. We hypothesize that CKD stage 2 is the tipping point in disease progression and a suitable point in disease course for the development of therapeutic solutions.
2022-08-12 | PXD033427 | Pride
Project description:We examined the transcriptional profile of human kidney biopsies, aiming to provide insight into the mechanisms of progressive CKD. This approach led to the identification of FERM domain protein 3, (FRMD3) as a molecular driver of disease. Transcriptome profiling was performed in human renal biopsy tissue and correlated with parameters of kidney function, including estimated glomerular filtration rate (eGFR), degree of renal tubulointerstitial fibrosis (%TIF), as well as CKD progression over a median follow-up period of 60 months. Transcriptome analysis performed in two independent cohorts of patients with CKD (n=24 and n=17, respectively) identified a cluster of genes (n=93) significantly correlated (FDR P<0.05) with eGFR and %TIF, and associated with CKD progression, with enrichment for pathways associated with inflammation and immune-cell mediated infiltration. Expression of FRMD3, a previously reported candidate gene from human genetics studies in CKD, was negatively correlated with indices of CKD severity and progression. Knockdown of FRMD3 in human kidney epithelial cells enhanced fibrotic responses to the cytokine transforming growth factor-beta (TGF-β1). Analysis of FRMD3 binding partners indicated enrichment of proteins implicated in mitochondrial function and remodeling of epithelial adherens junctions. Lentivirus-mediated knockdown of FRMD3 in renal tubule epithelial cells yielded a significant reduction (>35%) in NAD(P)H-dependent oxidoreductase activity, and a corresponding increase in caspase activity (50%). Using global transcriptome profiling we define a cluster of transcripts associated with severity of CKD and identify loss of FRMD3 expression as a potential molecular driver. Loss of FRMD3 expression may contribute to mitochondrial function and TIF.
2024-11-06 | PXD015297 | Pride
Project description:Trained immunity is the long-term functional reprogramming of innate immune cells, which results in altered responses toward a secondary challenge. Despite indoxyl sulfate (IS) being a potent stimulus associated with chronic kidney disease (CKD)-related inflammation, its impact on trained immunity has not been explored. Here, we demonstrate that IS induces trained immunity in monocytes via epigenetic and metabolic reprogramming, resulting in augmented cytokine production. Mechanistically, the aryl hydrocarbon receptor (AhR) contributes to IS-trained immunity by enhancing the expression of arachidonic acid (AA) metabolism-related genes such as Arachidonate 5-Lipoxygenase (ALOX5) and ALOX5 Activating Protein (ALOX5AP). Inhibition of AhR during IS training suppresses the induction of IS-trained immunity. Monocytes from end-stage renal disease (ESRD) patients have increased ALOX5 expression and after 6-day training, they exhibit enhanced TNF-α and IL-6 production to LPS. Furthermore, healthy control-derived monocytes trained with uremic sera from ESRD patients exhibit increased production of TNF-α and IL-6. Consistently, IS-trained mice and their splenic myeloid cells had increased production of TNF-α after in vivo and ex vivo LPS stimulation compared to that of control mice. These results provide insight into the role of IS in the induction of trained immunity, which is critical during inflammatory immune responses in CKD patients.
2024-06-20 | GSE263024 | GEO
Project description:Trained immunity is the long-term functional reprogramming of innate immune cells, which results in altered responses toward a secondary challenge. Despite indoxyl sulfate (IS) being a potent stimulus associated with chronic kidney disease (CKD)-related inflammation, its impact on trained immunity has not been explored. Here, we demonstrate that IS induces trained immunity in monocytes via epigenetic and metabolic reprogramming, resulting in augmented cytokine production. Mechanistically, the aryl hydrocarbon receptor (AhR) contributes to IS-trained immunity by enhancing the expression of arachidonic acid (AA) metabolism-related genes such as Arachidonate 5-Lipoxygenase (ALOX5) and ALOX5 Activating Protein (ALOX5AP). Inhibition of AhR during IS training suppresses the induction of IS-trained immunity. Monocytes from end-stage renal disease (ESRD) patients have increased ALOX5 expression and after 6-day training, they exhibit enhanced TNF-α and IL-6 production to LPS. Furthermore, healthy control-derived monocytes trained with uremic sera from ESRD patients exhibit increased production of TNF-α and IL-6. Consistently, IS-trained mice and their splenic myeloid cells had increased production of TNF-α after in vivo and ex vivo LPS stimulation compared to that of control mice. These results provide insight into the role of IS in the induction of trained immunity, which is critical during inflammatory immune responses in CKD patients.
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