Homo sapiens
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Project description:Renal hypoxia is widespread in acute kidney injury (AKI) of various aetiologies. Hypoxia adaptation, conferred through the hypoxia-inducible factor (HIF), appears to be insufficient. Here we show that HIF activation in renal tubules through Pax8-rtTA-based inducible knockout of von Hippel-Lindau protein (VHL-KO) protects from rhabdomyolysis-induced AKI. In this model, histological observations indicate that injury mainly affects proximal convoluted tubules, with 5% necrosis at d1 and 40% necrosis at d2. HIF-1alpha up-regulation in distal tubules reflects renal hypoxia. However, lack of HIF in proximal tubules suggests insufficient adaptation by HIF. AKI in VHL-KO mice leads to prominent HIF activation in all nephron segments, as well as to reduced serum creatinine, serum urea, tubular necrosis, and apoptosis marker caspase-3 protein. At d1 after rhabdomyolysis, when tubular injury is potentially reversible, HIF mediated protection in AKI is associated with activated glycolysis, cellular glucose uptake and utilization, autophagy, vasodilation, and proton removal as demonstrated by qPCR, pathway enrichment analysis and immunohistochemistry. Together, our data provide evidence for a HIF-orchestrated multi-level shift towards glycolysis as a major mechanism for protection against acute tubular injury. All experiments were carried out in transgenic mice in which selective renal tubular VHL knockout (VHL-KO) was inducible by doxycycline (Reference: Mathia S, Paliege A, Koesters R, Peters H, Neumayer HH, Bachmann S, Rosenberger C. Action of hypoxia-inducible factor in liver and kidney from mice with Pax8-rtTA-based deletion of von Hippel-Lindau protein. Acta Physiol (Oxf). 2013; 207(3):565-76.). Four groups of animals were used: 1) controls: untreated mice; 2) VHL-KO: injected with doxycycline (0.1 mg per 10 g body weight SC), 4 days prior to sacrifice; 3) AKI: rhabdomyolysis; 4) VHL-KO/AKI: doxycycline plus rhabdomyolysis. To induce AKI, 50% glycerol (0.05 ml per 10 g body weight) was injected IM into the left hind limb under isoflurane narcosis. Drinking water was withdrawn between 20 h prior and 24 h after glycerol injection.
2013-09-05 | E-GEOD-44925 | biostudies-arrayexpress
Project description:Renal hypoxia is widespread in acute kidney injury (AKI) of various aetiologies. Hypoxia adaptation, conferred through the hypoxia-inducible factor (HIF), appears to be insufficient. Here we show that HIF activation in renal tubules through Pax8-rtTA-based inducible knockout of von Hippel-Lindau protein (VHL-KO) protects from rhabdomyolysis-induced AKI. In this model, histological observations indicate that injury mainly affects proximal convoluted tubules, with 5% necrosis at d1 and 40% necrosis at d2. HIF-1alpha up-regulation in distal tubules reflects renal hypoxia. However, lack of HIF in proximal tubules suggests insufficient adaptation by HIF. AKI in VHL-KO mice leads to prominent HIF activation in all nephron segments, as well as to reduced serum creatinine, serum urea, tubular necrosis, and apoptosis marker caspase-3 protein. At d1 after rhabdomyolysis, when tubular injury is potentially reversible, HIF mediated protection in AKI is associated with activated glycolysis, cellular glucose uptake and utilization, autophagy, vasodilation, and proton removal as demonstrated by qPCR, pathway enrichment analysis and immunohistochemistry. Together, our data provide evidence for a HIF-orchestrated multi-level shift towards glycolysis as a major mechanism for protection against acute tubular injury.
2013-09-05 | GSE44925 | GEO
Project description:Intestinal epithelia exist in a uniquely dynamic oxygen tension microenvironment. Adaptive responses to hypoxia in mammalian cells are regulated largely by hypoxia inducible factor (HIF) transcriptional complexes. Functional HIF exists as an obligate alpha/beta heterodimer, comprising both a constitutive subunit (HIF-1beta), and an oxygen-labile regulatory (alpha) component. To date, three regulatory subunits have been identified, namely HIF-1alpha, HIF-2alpha, and HIF-3alpha, with the highest level of sequence homology conserved between HIF-1alpha and HIF-2alpha. Despite their concurrent expression in intestinal epithelial cells, HIF-1 and HIF-2 play non-redundant roles in the regulation of an overlapping but distinct set of gene targets. In this study, we performed ChIP-on-chip analysis of chromatin isolated from hypoxic intestinal epithelia to delineate HIF-1 and HIF-2 specific loci. Comparison of HIF-1alpha ChIP-chip and HIF-2alpha ChIP-chip to map HIF-1- and HIF-2-specific gene targets across the genome.
2013-11-05 | E-GEOD-43108 | biostudies-arrayexpress
Project description:We performed HIF-1alpha ChIP-seq in SK-N-BE(2) cells cultured in normoxia vs. hypoxia for 48 hrs. We identified two new HIF-1alpha binding sites in TET1 that control TET1expression in hypoxia
2022-08-10 | GSE167477 | GEO
Project description:Widespread intraperitoneal metastases and chemoresistance has made ovarian cancer the leading cause of gynecological malignancy–related deaths, wherein TGF-β signaling plays the pivotal role by promoting cancer stem cells (CSCs) activity. Whereas, how the signaling is activated and how to target TGF-β signaling precisely remain as key challenges. Here, we identify hypoxic tumor microenvironment as the initiator of TGF-β signaling so as to induce HIF-2α positive CSCs and chemoresistance in HGSOC. Mechanistically, deubiquitinase USP9X, as the TGF-β downstream effector, stabilizes HIF-2ɑ in hydroxylation and ubiquitylation dependent manner, thus activates stemness programming. Hypoxia and TGF-β signals promote USP9X-HIF-2ɑ axis via multi-level regulations, which in turn facilitates Smad/HIF responses, thus coordinating the two pathways. Clinical USP9X is highly correlated with TGF-β signatures, CSCs characteristics, EMT behaviors, and stimulated by chemotherapies, along with HIF-2ɑ. Antagonizing USP9X efficiently represses tumor formation, metastasis, CSCs occurrence, while increases chemosensitivity, through orthotopic tumor, patient derived xenograft (PDX), organoid and chemoresistant cell models, via restricting TGF-β and hypoxia activities. This study deciphers the critical role of hypoxic niche in turning up TGF-β signaling, as well as USP9X-HIF-2ɑ proteostatic regulation in priming the HGSOC stemness, thus provides a promising strategy to counteract TGF-β signaling by targeting USP9X in CSCs and meliorate clinical chemoresistance.
2024-03-08 | PXD050476 |
Project description:The activation of hypoxia-inducible transcription factors (HIF) leading to the expression of hundreds of target genes is a fundamental mechanism in acute and chronic kidney disease, mediating protective but possibly harmful effects. Furthermore, dysregulation of the HIF pathway in chronic kidney disease causes renal anemia through insufficient erythropoietin (EPO) induction in interstitial cells. RNA-seq analysis was performed in human primary renal tubular cells to analyse the effect of HIF stabilization on the expression of genes in tubular cells. ATAC-seq and HIF-CHIP-seq complement the data to analyse transcription factor binding and chromatin configuration changes.
2023-05-05 | GSE227821 | GEO
Project description:The activation of hypoxia-inducible transcription factors (HIF) leading to the expression of hundreds of target genes is a fundamental mechanism in acute and chronic kidney disease, mediating protective but possibly harmful effects. Furthermore, dysregulation of the HIF pathway in chronic kidney disease causes renal anemia through insufficient erythropoietin (EPO) induction in interstitial cells. RNA-seq analysis was performed in human primary renal tubular cells to analyse the effect of HIF stabilization on the expression of genes in tubular cells. ATAC-seq and HIF-CHIP-seq complement the data to analyse transcription factor binding and chromatin configuration changes.
2023-05-05 | GSE227848 | GEO
Project description:The activation of hypoxia-inducible transcription factors (HIF) leading to the expression of hundreds of target genes is a fundamental mechanism in acute and chronic kidney disease, mediating protective but possibly harmful effects. Furthermore, dysregulation of the HIF pathway in chronic kidney disease causes renal anemia through insufficient erythropoietin (EPO) induction in interstitial cells. RNA-seq analysis was performed in human primary renal tubular cells to analyse the effect of HIF stabilization on the expression of genes in tubular cells. ATAC-seq and HIF-CHIP-seq complement the data to analyse transcription factor binding and chromatin configuration changes.
2023-05-05 | GSE227823 | GEO
Project description:Comprehensive analysis of coding and non -coding transcriptome using ribo-depleted total RNA-seq and poly A selected RNA-seq of MCF-7 cells grown in hypoxia and normoxia. Breast cancer cell line (MCF-7) is cultured in normoxic condition (21% O2) and hypoxic condition (1%O2) for 24 hours. Expression of HIF-1alpha and/or HIF-2alpha subunits was suppressed using siRNAs in hypoxic MCF-7 cells. Total RNA was isolated from both hypoxia and normoxia conditions were subjected for ribosomal depleted stand specific RNA-seq and poly A selected RNA-seq
2014-02-10 | E-MTAB-1994 | biostudies-arrayexpress
Project description:Activation of hypoxia-inducible transcription factors (HIF) leading to expression of hundred of target genes is a fundamental mechanism in acute and chronic kidney disease mediating protective but also possibly harmful effects. Furthermore, dysregulation of the HIF pathway in chronic kidney disease causes renal anemia through insufficient induction of erythropoietin (EPO) in interstitial cells. Hence, pharmacological compounds to treat renal anemia by stabilizing HIF have recently been introduced to the clinical practice. RNA-seq analysis was performed in primary renal tubular cells to analyse the effect of HIF stabilization on the expression of pathogenic Mucin1 (MUC1) variants. This study links the regulation of the kidney-disease gene MUC1 with the HIF-pathway in renal tubular cells.
2023-06-07 | GSE224177 | GEO