Tubular epithelial NF-κB activity regulates acute ischemic kideny injury
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ABSTRACT:
PROVIDER: PRJNA343239 | ENA |
REPOSITORIES: ENA
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Project description:NF-κB is a key regulator of innate and adaptive immunity and is implicated in the pathogenesis of acute kidney injury (AKI). The cell type-specific functions of NF-κB in the kidney are unknown; however, the pathway serves distinct functions in immune and tissue-parenchymal cells. We analyzed tubular epithelial-specific NF-κB signaling in a mouse model of ischemia-reperfusion injury (IRI)-induced AKI. NF-κB reporter activity and nuclear localization of phosphorylated NF-κB subunit p65 analyses in mice revealed widespread NF-κB activation in renal tubular epithelia and in interstitial cells following IRI that peaked at 2-3 days after injury. To genetically antagonize tubular epithelial NF-κB activity, we generated mice expressing the human NF-κB super-repressor IκBα∆N in renal proximal, distal, and collecting duct epithelial cells. These mice were protected from IRI-induced AKI, as indicated by improved renal function, reduced tubular apoptosis, and attenuated neutrophil and macrophage infiltration. Tubular NF-κB-dependent gene expression profiles revealed temporally distinct functional gene clusters for apoptosis, chemotaxis, and morphogenesis. Primary proximal tubular cells isolated from IκBα∆N-expressing mice exposed to hypoxia-mimetic agent cobalt chloride were protected from apoptosis and expressed reduced levels of chemokines. Our results indicate that postischemic NF-κB activation in renal-tubular epithelia aggravates tubular injury and exacerbates a maladaptive inflammatory response.
2016-09-17 | GSE87024 | GEO
Project description:NF-κB is a key regulator of innate and adaptive immunity and is implicated in the pathogenesis of acute kidney injury (AKI). The cell type-specific functions of NF-κB in the kidney are unknown; however, the pathway serves distinct functions in immune and tissue-parenchymal cells. We analyzed tubular epithelial-specific NF-κB signaling in a mouse model of ischemia-reperfusion injury (IRI)-induced AKI. NF-κB reporter activity and nuclear localization of phosphorylated NF-κB subunit p65 analyses in mice revealed widespread NF-κB activation in renal tubular epithelia and in interstitial cells following IRI that peaked at 2-3 days after injury. To genetically antagonize tubular epithelial NF-κB activity, we generated mice expressing the human NF-κB super-repressor IκBα∆N in renal proximal, distal, and collecting duct epithelial cells. These mice were protected from IRI-induced AKI, as indicated by improved renal function, reduced tubular apoptosis, and attenuated neutrophil and macrophage infiltration. Tubular NF-κB-dependent gene expression profiles revealed temporally distinct functional gene clusters for apoptosis, chemotaxis, and morphogenesis. Primary proximal tubular cells isolated from IκBα∆N-expressing mice exposed to hypoxia-mimetic agent cobalt chloride were protected from apoptosis and expressed reduced levels of chemokines. Our results indicate that postischemic NF-κB activation in renal-tubular epithelia aggravates tubular injury and exacerbates a maladaptive inflammatory response.
2016-09-17 | GSE87023 | GEO
Project description:Acute kidney injury (AKI) is a common clinical condition associated with high morbidity and mortality. However, its pathogenesis is still incompletely understood. Increased expression of CXCR2 has been reported in acute kidney injury (AKI), but its regulatory mechanism remains unclear. Here we found that increased CXCR2 in tubular cells, as seen in ischemia-reperfusion injury (IRI)-induced or cisplatin-induced AKI, was colocalized with apoptosis and autophagy related indicators. In human AKI, CXCR2 was found present in tubular cells in kidney biopsy tissue and positively correlated with the severity of AKI. Tubular-specific CXCR2 knockout mice decreased the severity of IRI-induced AKI as characterized by lower kidney injury, interstitial inflammation, apoptosis and higher renal function. Furthermore, analysis of murine nephrotoxic AKI transcriptomics indicated autophagy as highly upregulated and ERK1/2/NF-κB signaling downregulated. On the other hand, overexpression CXCR2 with pFlag-CXCR2 plasmid aggravated renal function damage by regulating ERK1/2/ NF-κB p65-mediating autophagy in IRI-induced or cisplatin-induced AKI mice model. Treatment of AZD5069 ameliorated apoptosis and promoted autophagy in the AKI model. siCXCR2 significantly promoted autophagy and inhibited apoptosis and injury in cultured H/R treated-HKC-8 cells. Mechanistically, p-ERK1/2 promoted p-p65 transferred into nucleus, resulting in p65 directly binding to the promoter region of ATG5 gene which is an important molecule in the regulation of autophagy in vitro. Thus, our findings demonstrate that deletion or inhibition CXCR2 increasing autophagy by attenuating tubular injury, inflammation, and apoptosis in AKI. Hence, our study identifies CXCR2 as a critical regulator of autophagy and provides a potent strategy for preventing tubular injury in AKI.
2026-02-28 | GSE289296 | GEO
Project description:Tubular epithelial NF-κB activity regulates acute ischemic kideny injury [OTT-211009]
| PRJNA343242 | ENA
Project description:Tubular epithelial NF-κB activity regulates acute ischemic kideny injury [130402-EV-EmxdN]
| PRJNA343243 | ENA
Project description:Non-consensus binding sites of transcription factors are often observed within the promoters and enhancers of various genes; however, their effect on transcriptional strength is unclear. Within the promoters and enhancers of NF-κB-responsive genes, we identified clusters of non- consensus κB DNA sites, many exhibiting low affinity for NF-κB in vitro. Deletion of these sites demonstrated their collective critical role in transcription. We explored how these “weak” κB sites exert their influence, especially given the typically low nuclear concentration of NF-κB. Using proteomics approaches, we identified additional nuclear factors, including other DNA-binding TFs, that could interact with κB site-bound NF-κB RelA without their direct interaction to DNA. ChIP- seq and RNA-seq analyses suggest that these accessory TFs, referred to as the TF-cofactors of NF-κB, facilitate dynamic recruitment of NF-κB to the clustered κB sites. Overall, the occupancy of NF-κB at promoters and enhancers appears to be defined by a collective contribution from all κB sites, both weak and strong, in association with specific cofactors. This congregation of multiple factors within dynamic transcriptional complexes is likely a common feature of transcriptional programs.
2025-10-13 | PXD065004 | Pride
Project description:NF-κB has an essential role in innate immune response and inflammation and is involved in cancer development and progression. We apply the SEC-PCP-SILAC method incorporating metabolic labeling, size exclusion chromatography and protein correlation profiling to construct a complex network of interactome rearrangement in response to NF-κB modulation in breast cancer cells. Our interaction network represents a complex insight into the dynamics of MCF-7 protein interactome associated with NF-κB pathway. Our dataset could serve as a basis for future studies characterizing role of NF-κB in breast cancer cellular pathways. This PRIDE project includes results from SILAC labeled and label-free replicates from the SEC-PCP-SILAC analysis of protein complexes in MCF-7 cells with inhibited and uninhibited NF-κB pathway, results from the immunoprecipitation experiment aimed at interaction partners of NF-κB factor RELA, analysis of total proteome after NF-κB inhibition, and results from SEC fractionation of untreated and unlabeled MCF-7 cells.
2024-02-28 | PXD040125 | Pride
Project description:Transcriptional profiling of human control and Néstor-Guillermo Progeria Syndrome (NGPS) fibroblasts and induced pluripotent stem cells (iPSCs). Somatic cell reprogramming involves rejuvenation of adult cells and relies on the ability to erase age-associated molecular marks. Accordingly, reprogramming efficiency declines with ageing, and age-associated features such as genetic instability, cell senescence or telomere shortening negatively affect this process. However, the regulatory mechanisms that constitute age-associated barriers for cell reprogramming remain largely unknown. Here, by using cells from patients with premature ageing, we demonstrate that NF-κB activation is a critical barrier for the generation of induced pluripotent stem cells (iPSCs) in ageing. We show that NF-κB repression occurs during cell reprogramming towards a pluripotent state. Conversely, ageing-associated NF-κB hyperactivation impairs generation of iPSCs by eliciting reprogramming repressors DOT1L and YY1, reinforcing cell senescence signals and down-regulating pluripotency genes. We also show that genetic and pharmacological NF-κB inhibitory strategies significantly increase the reprogramming efficiency of fibroblasts from Néstor-Guillermo Progeria Syndrome (NGPS) and Hutchinson-Gilford Progeria Syndrome (HGPS) patients, as well as from normal aged donors. Finally, we demonstrate that DOT1L inhibition in vivo ameliorates the accelerated ageing phenotype and extends lifespan in a progeroid animal model. Collectively, our results provide evidence for a novel role of NF-κB in the control of cell fate transitions and reinforce the interest of studying age-associated molecular impairments to implement cell reprogramming methodologies, and to identify new targets of rejuvenation strategies. Control and NGPS fibroblasts were reprogrammed. RNA was extracted and transcriptional profiling was obtained with GeneChip Human Exon 1.0 ST Arrays.
2015-07-01 | E-GEOD-65170 | biostudies-arrayexpress
Project description:Transcriptional profiling of human control and Néstor-Guillermo Progeria Syndrome (NGPS) mesenchymal stem cells (MSCs). Somatic cell reprogramming involves rejuvenation of adult cells and relies on the ability to erase age-associated molecular marks. Accordingly, reprogramming efficiency declines with ageing, and age-associated features such as genetic instability, cell senescence or telomere shortening negatively affect this process. However, the regulatory mechanisms that constitute age-associated barriers for cell reprogramming remain largely unknown. Here, by using cells from patients with premature ageing, we demonstrate that NF-κB activation is a critical barrier for the generation of induced pluripotent stem cells (iPSCs) in ageing. We show that NF-κB repression occurs during cell reprogramming towards a pluripotent state. Conversely, ageing-associated NF-κB hyperactivation impairs generation of iPSCs by eliciting reprogramming repressors DOT1L and YY1, reinforcing cell senescence signals and down-regulating pluripotency genes. We also show that genetic and pharmacological NF-κB inhibitory strategies significantly increase the reprogramming efficiency of fibroblasts from Néstor-Guillermo Progeria Syndrome (NGPS) and Hutchinson-Gilford Progeria Syndrome (HGPS) patients, as well as from normal aged donors. Finally, we demonstrate that DOT1L inhibition in vivo ameliorates the accelerated ageing phenotype and extends lifespan in a progeroid animal model. Collectively, our results provide evidence for a novel role of NF-κB in the control of cell fate transitions and reinforce the interest of studying age-associated molecular impairments to implement cell reprogramming methodologies, and to identify new targets of rejuvenation strategies. Control and NGPS MSCs were differentiated into bone in the presence or absence of sodium salicylate. Total RNA was extracted and global gene expression was analyzed.
2015-07-01 | E-GEOD-65172 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the SubSeries listed below.
2016-09-17 | GSE87025 | GEO