Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Runt-related Transcription Factor 1 (RUNX1) is a mediator of acute kidney injury

ABSTRACT: Treatment for acute kidney injury (AKI) is suboptimal. A better understanding of its pathogenesis may lead to new therapeutic approaches. Kidney transcriptomics analyses of murine folic acid-induced AKI (FA-AKI) identified Runx1 as the most upregulated RUNX family gene. RUNX1 overexpression in FA-AKI was validated at the mRNA and protein levels and localized mainly to tubular cell nuclei. Bacterial lipopolysaccharide (LPS)-induced cytokine storm-AKI also upregulated kidney RUNX1. Increased tubular and interstitial RUNX1 expression were also observed in human AKI. In cultured murine tubular cells, the proinflammatory cytokine TWEAK and LPS increased RUNX1 and IL-6 expression. Mechanistically, RUNX1 bound to the Il-6 gene promoter while RUNX1 targeting with either the chemical inhibitor Ro5-3335 or a specific small interfering RNA (siRNA) prevented the TWEAK- and LPS-induced upregulation of IL-6 through a RUNX1/NFκB p50 pathway. TWEAK and LPS also induced RUNX1 binding to the promoter of Cdkn1a which encodes the cyclin-dependent kinase inhibitor p21 and increased p21 expression. In vivo, preventive Ro5-3335 improved kidney function and reduced inflammation and p21 expression in both FA-AKI, and in cytokine storm-AKI. However, administration of Ro5-3335 after the insult only improved kidney function in cytokine storm-AKI. Kidney transcriptomics identified inflammatory genes and the transcription factor Yap1 as key targets of Ro5-3335 in cytokine storm-AKI. In conclusion, RUNX1 contributes to AKI by driving the expression of genes involved in inflammation and represents a novel therapeutic target in AKI.

ORGANISM(S): Mus musculus

PROVIDER: GSE243633 | GEO | 2025/02/12

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Next Generation Sequencing Facilitates Quantitative Analysis of primary cultured astrocytes treated with SB431542, Ro5-3335 and HLM006474 inhibitors.

Project description:Purpose: The goals of this study are to investigate differential genes expression with RNA-seq in primary cultured astrocytes treated with the Tgf-beta1 receptor inhibitor SB431542, the Runx1 inhibitor Ro5-3335 and the E2f1 inhibitor HLM006474. Methods: Primary cultured astrocytes were isolated from either C57BL/6 wild-type neonatal mice. Total RNA was extracted from SB431542, Ro5-3335 and HLM006474-treated astrocytes with the RNeasy Plus Micro Kit (Qiagen; 74034). mRNA profiles were generated by deep sequencing using Illumina NovaSeq 6000. The sequence reads that passed quality filters were aligned to the mouse reference genome (GRCm38) using the STAR software package. Differential expression analysis were performed using the R package DESeq2. qPCR validation was performed using SYBR Green assays. Results: After quality control and data filtering, about 50 million raw reads per sample were obtained. We mapped sequence reads per sample to the mouse reference genome (GRCm38) and identified 35825 transcripts vehicle, SB431542, Ro5-3335 and HLM006474 group. Differentially expressed genes (DEGs) were analyzed with a fold change ≥1.5 and p value <0.05. A total of 748 DEGs were identified in SB431542 group with 347 upregulated genes and 401 downregulated genes. A total of 397 DEGs were identified in Ro5-3335 group with 82 upregulated genes and 315 downregulated genes. A total of 856 DEGs were identified in HLM006474 group with 216 upregulated genes and 640 downregulated genes. Hierarchical clustering heat map, pathway enrichment and analysis of DEGs were performed. Conclusions: Our RNA-seq dataset represents the differentially expressed genes in the C57BL/6 astrocytes treated with SB431542, Ro5-3335 and HLM006474-treated astrocytes.

2022-11-23 | GSE174523 | GEO

Profile of gene expression in murine tubular cells MCTs treated with the cytokine TWEAK

Project description:Treatment of acute kidney injury (AKI) is suboptimal. TWEAK is known to mediate cell death and inflammation in AKI. Transcriptomic analysis of murine tubular cells will allow us to identify novel mediators and therapeutic targets of this pathology. TWEAK is an inflammatory cytokine which is upregulated in AKI. Transcriptomic analysis of TWEAK-stimulated cultured murine tubular epithelial cells identified downregulation of peroxisome proliferator activated receptor-g coactivador-1a (PGC-1a) and its target genes (mitochondrial proteins Ndufs1, Sdha, and Tfam) as a shared feature.

2024-07-29 | GSE273064 | GEO

Proteomic analysis of septic renal acute phase response

Project description:Sepsis-induced acute kidney injury (AKI) is the most common form of AKI with poor outcomes. Renal proteomic analysis after bacterial lipopolysaccharide (LPS) administration revealed that the local renal acute phase reaction (APR) is one of the strongest responses of the kidney during septic AKI in mice. Evaluation of mRNA expression confirmed that most acute phase proteins were produced in the kidney. Our study also provides missing information on the time course of septic renal APR. Proteomic analysis of LPS-induced AKI demonstrated a marked upregulation of local renal acute phase response (APR) that commenced a few hours post injection and peaked at 24 h. Much more APPs were involved in the renal APR than previously identified.

2020-01-08 | PXD014664 | Pride

Profile of gene expression in experimental acute kidney injury

Project description:Treatment for acute kidney injury (AKI) is suboptimal. A better understanding of its pathogenesis may lead to new therapeutic approaches. Kidney transcriptomics analyses of murine folic acid-induced AKI (FA-AKI) will allow us to identify new mediators and therapeutic targets of this pathology. Folic acid nephropathy is a classical model of AKI characterized by acute renal failure, tubular cell death, interstitial leukocyte infiltration and subsequent tubular regeneration that has been reported in humans.

2024-07-29 | GSE273063 | GEO

The collaboration of GSDMD and GSDME in folic acid (FA)-induced renal injury

Project description:Acute kidney injury(AKI) is associated with an increased risk of chronic kidney disease(CKD). There is still a lack of effective prevention for AKI-CKD transition. In the present study, we simultaneously explored the contribution of GSDMD and GSDME in folic acid (FA)-induced nephropathy, a model mimicking the essential components of the AKI-CKD transition. We found that blockage of both GSDMD and GSDME-mediated pyroptosis could have accumulative protection against FA-induced AKI-CKD transition. GSDME-mediated pyroptosis played a crucial role in tubular cell damage. GSDMD could exert important functions in infiltration of inflammatory cells and NETs formation. Pyroptotic tubular cells triggered NETs generation and macrophage polarization. NETs promoted macrophage-to-myofibroblast transition. Our results illustrated the orchestration of GSDMD and GSDME in AKI-CKD transition, providing new insights into the molecular mechanism for the clinical dilemma.

2024-10-31 | GSE245446 | GEO

Microarray-based clustering analysis of miRNAs altered in IRI-AKI mouse kidney

2021-05-14 | GSE172039 | GEO

Microarray-based clustering analysis of miRNAs altered in LPS-AKI mouse kidney

2021-05-14 | GSE172038 | GEO

Overexpression of miRNA-5100 with PEI-NPs led to change in expression of many mRNAs

Project description:The aim of this study was to identify miRNAs that regulate AKI and develop their applications as diagnostic biomarkers and therapeutic agents. First, kidney tissues from two different AKI mouse models, namely, AKI induced by the administration of lipopolysaccharide (LPS) causing sepsis (LPS-AKI mice) and AKI induced by renal ischemia–reperfusion injury (IRI-AKI mice), were exhaustively screened for their changes of miRNA expression compared with that of control mice by microarray analysis followed by quantitative RT-PCR. The initial profiling newly identified miRNA-5100, whose expression levels significantly decreased in kidneys in both LPS-AKI mice and IRI-AKI mice. Next, the administration of miRNA-5100-mimic conjugated with a nonviral vector, polyethylenimine nanoparticles (PEI-NPs), via the tail vein significantly induced miRNA-5100 overexpression in the kidney and prevented the development of IRI-AKI mice by inhibiting apoptosis and inflammation in vivo. Furthermore, serum levels of miRNA-5100 in patients with AKI were identified as significantly lower than those of healthy subjects. ROC analysis showed that the serum expression level of miRNA-5100 can identify AKI (cut-off value 0.14, AUC 0.96, sensitivity 1.00, specificity 0.833, p<0.05). These results suggest that miRNA-5100 regulates AKI and may be useful as a novel diagnostic biomarker and therapeutic target for AKI.

2021-05-14 | GSE172042 | GEO

RUNX1 expression is regulated by a super-enhancer and is a therapeutic target in adult T-cell leukemia/lymphoma

Project description:Super-enhancers (SEs)—genomic enhancer regions with dense accumulation of mediator complexes—play an important role in regulating tumor-specific gene expression and are potential therapeutic targets for neoplastic diseases. Bromodomain-containing protein 4 (BRD4) is a component of the protein complexes that bind to the SE region. JQ1, one of the known BRD4 inhibitors, exerts antitumor effects by suppressing SE-mediated regulation of gene expression. Adult T-cell leukemia/lymphoma (ATL) is highly resistant to available treatments, and its prognosis is extremely poor. As JQ1 has potential as a therapeutic agent for various malignancies, we investigated the anti-ATL effects of JQ1. JQ1 induced apoptosis and inhibited ATL cell proliferation. JQ1 suppressed the expression of RUNX1 through the disruption of SE-mediated gene regulation, indicating that RUNX1 could be a novel therapeutic target molecule. AI-10-104 and Ro5-3335 are RUNX1 inhibitors developed for hematologic malignancies such as acute myeloid leukemia (AML) and lymphoblastic leukemia (ALs). We demonstrated that these two agents reduced cell proliferation in ATL cell lines and patient samples at effective concentrations in ALs with RUNX1 mutations. Simultaneously, AI-10-104 suppressed MYC proto-oncogene (c-MYC) expression. RUNX1 is a potential therapeutic target for ATL that promotes c-MYC expression. For the first time, we showed that RUNX1 expression is regulated via SEs in ATL, a hematologic malignancy of peripheral mature T cells. This study indicates that RUNX1 may be a novel therapeutic target for ATL.

2025-01-13 | GSE253457 | GEO

ARPCs Can Revert Lps-Induced Endothelial-to-Mesenchymal Transition of Endothelial Cells

Project description:Endothelial dysfunction is a hallmark of LPS-induced acute kidney injury (AKI). Endothelial cells (EC) acquired a fibroblast-like phenotype and contributed to myofibroblasts generation through Endothelial to Mesenchymal Transition (EndMT) process. Noteworthy, ARPCs enhance tubular regenerative mechanism during AKI, but little is known about their effects on EC. Here we investigated whether ARPCs could prevent sepsis-induced EndMT and the related mechanism. When activated by LPS, Human endothelial cells (EC) proliferated and decreased specific EC markers such as CD31 and VE-cadherin and up-regulated myofibroblast markers such as Collagen I and Vimentin. The co-culture with ARPCs normalized EC proliferation rate and abrogated the LPS-induced EndMT by restoring the high expression of EC markers and the low expression of myofibroblast markers. Gene set enrichment analysis showed that most of genes modulated in LPS-stimulated ARPCs belongs to cell activation and defense response pathways. In particular, among most up-regulated genes we found BPIFA2, SAA2, SAA4 and CXCL6. BPIFA2 is recently described as an early biomarker of AKI but little is known about its function in the kidney. The other genes are frequently involved in the response to bacterial infection and kidney injury. Finally, in a swine model of LPS-induced AKI, we observed an increase of CD133+ARPCs that expressed BPIFA2 respect to healthy pigs. Taken together, these results suggest an underestimate role of ARPCS in preventing endothelial dysfuncton by the production of several proteins. The identification of these molecules may offer novel strategies to protect endothelial compartment and promote kidney repair.

2019-07-01 | GSE116849 | GEO