Mus musculus
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PROVIDER: PRJNA343243 | ENA |
REPOSITORIES: ENA
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Project description:Tubular epithelial NF-κB activity regulates acute ischemic kideny injury
| PRJNA343239 | ENA
Project description:Tubular epithelial NF-κB activity regulates acute ischemic kideny injury [OTT-211009]
| PRJNA343242 | ENA
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:Renal warm ischemia-reperfusion (I/R) injury drives acute kidney injury and transplant dys-function through endoplasmic reticulum (ER) stress. Although Activating Transcription Factor 6 (ATF6) modulates ER stress resolution via the unfolded protein response, its functional role in re-nal IRI remains undefined. Using murine model of warm renal I/R and hypoxia-reoxygenation (H/R)-treated HUVECs/HK-2 cells, we systematically investigated the expression of ATF6 and molecular mechanisms through RNA-seq, ChIP, and dual-luciferase assays. IRI significantly up-regulated the expression of ATF6 in renal tissues, especially in proximal tubule epithelial cells. Functionally, ATF6 activation reduced Cr, BUN, and inflammatory cytokines, whereas genet-ic/pharmacological suppression aggravated renal tubular damage. Mechanistic studies revealed ATF6 transcriptionally represses FHL2 by direct promoter binding. The interaction between FHL2 and TRAF6 promoted the TRAF6/NF-κB signaling pathway, and the phosphorylation levels of p65 and IκBα were increased. ATF6 overexpression effectively counteracted FHL2-mediated NF-κB hyperactivation, establishing a protective axis where ATF6 mitigates inflammation via FHL2 sup-pression. This study identifies ATF6 as a renoprotective factor that suppresses FHL2 to inhibit TRAF6/NF-κB inflammation during IRI. The ATF6/FHL2/NF-κB axis provides mechanistic in-sights and therapeutic targets for ischemic renal injury and transplant complications.
2026-02-13 | GSE308759 | 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:Nf-kB activity is associated with the key pathological features of chronic respiratory diseases including epithelial remodelling, excess mucous production, and submucosal gland hyperplasia. However, the role of Nf-kB activity in airway epithelial differentiation remains controversial. In the present study we demonstrate that Nf-kB adaptor protein Myd88 deficiency promotes increased airway submucosal gland abundance and abnormal epithelial differentiation in proximal adult airways. Abnormal airway differentiation was not developmentally determined, became exacerbated following acute lung injury, and did not involve altered epithelial proliferation or apoptosis. Instead, we demonstrate that tracheal Myd88 deficiency promotes upregulation of a unique gene expression profile that includes activation of alternate, Myd88-independent Nf-kB signalling. Finally, we show that these effects are not intrinsically maintained in vitro using an air-liquid interface epithelial culture. This finding indicates that Myd88 deficiency promotes adult airway remodelling by regulating non-epithelial, non-cell autonomous Nf-kB activity. 20 microarray samples of whole trachea RNA in total: 5 samples wildtype control tissue 5 samples Myd88 KO control tissue 5 samples wildtype 3 day polidocanol injury tissue 5 samples Myd88 KO 3 day polidocanol injury tissue
2011-03-17 | E-GEOD-17268 | biostudies-arrayexpress
Project description:The mechanistic target of rapamycin mTORC1 is a key regulator of cell metabolism and autophagy. Despite widespread clinical use of mTOR inhibitors, the role of mTORC1 in renal tubular function and kidney homeostasis remains elusive. By utilizing constitutive and inducible deletion of conditional Raptor alleles in renal tubular epithelial cells, we discovered that mTORC1 deficiency caused a marked concentrating defect, loss of tubular cells and slowly progressive renal fibrosis. Transcriptional profiling revealed that mTORC1 maintains renal tubular homeostasis by controlling mitochondrial metabolism and biogenesis as well as transcellular transport processes involved in counter-current multiplication and urine concentration. Although mTORC2 partially compensated the loss of mTORC1, exposure to ischemia and reperfusion injury exaggerated the tubular damage in mTORC1-deficient mice, and caused pronounced apoptosis, diminished proliferation rates and delayed recovery. These findings identify mTORC1 as an essential regulator of tubular energy metabolism and as a crucial component of ischemic stress responses. Pharmacological inhibition of mTORC1 likely affects tubular homeostasis, and may be particularly deleterious if the kidney is exposed to acute injury. Furthermore, the combined inhibition of mTORC1 and mTORC2 may increase the susceptibility to renal damage. Raptor fl/fl*KspCre and Raptor fl/fl animals were sacrificed at P14 before the development of an overt functional phenotype. Kidneys were split in half and immediately snap frozen in liquid nitrogen.
2014-06-09 | E-GEOD-54417 | biostudies-arrayexpress
Project description:The role of matrilin-3 in the brain, an extracellular matrix component in cartilage, is unknown. Here, we identify matrilin-3 decreased in reactive astrocytes but unchanged in neurons after ischemic stroke in animals. Importantly, it is declined in serum of patients with acute ischemic stroke. Genetic or pharmacological inhibition or supplementation of matrilin-3 aggravates or reduces brain injury, astrocytic cell death and glial scar, respectively, but has no direct effect on neuronal cell death. RNA-sequencing demonstrates that Matn3−/− mice display an increased inflammatory response profile in the ischemic brain, including the NF-κB signaling pathway. Both endogenous and exogenous matrilin-3 reduce inflammatory mediators. Mechanistically, extracellular matrilin-3 enters astrocytes via caveolin-1-mediated endocytosis. Cytoplasmic matrilin-3 translocates into the nucleus by binding to NF-κB p65, suppressing inflammatory cytokines transcription. Extracellular matrilin-3 binds to BMP-2, blocking BMP-2/Smads pathway. Thus, matrilin-3 is required for astrocytes to exert neuroprotection at least partially via suppressing astrocyte-mediated neuroinflammation.
2024-02-22 | GSE253799 | GEO
Project description:The mechanism underlying circRNA-mediated maintenance of mitochondrial function remains largely unknown. Our study found circAASS was downregulated in renal cortex from mice suffered ischemic reperfusion (IR)-induced acute kidney injury (AKI). Functional study demonstrated that circAASS regulated mitochondrial homeostasis in tubular epithelial cells (TECs). Therefore, to reveal the mechanisms underlying the anti-injury effects of circAASS in TECs. circAASS was overexpressed in hypoxia/reperfusion treated- human immortalized cell line HK2 cells. RNA sequencing was performed and the dysregulated mRNAs were found.
2026-03-01 | GSE286356 | GEO