Unidentified
Ontology highlight
ABSTRACT:
PROVIDER: PRJDB19254 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| DRR670283_1.fastq.gz | Fastqsanger.gz | |||
| DRR670283_2.fastq.gz | Fastqsanger.gz | |||
| DRR670284_1.fastq.gz | Fastqsanger.gz | |||
| DRR670284_2.fastq.gz | Fastqsanger.gz | |||
| DRR670285_1.fastq.gz | Fastqsanger.gz |
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Project description:Cardiovascular complications are the leading cause of death in autosomal dominant polycystic kidney disease (ADPKD), and intracranial aneurysm (ICA) causing subarachnoid hemorrhage is among the most serious complications. The diagnostic and therapeutic strategies for ICAs in ADPKD have not been fully established. We here generated induced pluripotent stem cells (iPSCs) from seven ADPKD patients, including four with ICAs. The vascular cells differentiated from ADPKD-iPSCs showed altered Ca2+ entry and gene expression profiles compared with those from control-iPSCs. We found that the expression level of a metalloenzyme gene, matrix metalloproteinase (MMP) 1, was specifically elevated in the iPSC-derived endothelia from ADPKD patients with ICAs. Furthermore, we confirmed a statistically significant correlation between the serum MMP1 levels and the development of ICAs in 354 ADPKD patients, indicating that the serum MMP1 levels may be a novel risk factor and become more beneficial when combined with other risk factors. These results suggest that cellular disease models with ADPKD-specific iPSCs can be used to study the disease mechanisms and to identify novel disease-related molecules or risk factors. The gene expression profiles of vascular endothelia and smooth muscle cells derived from ADPKD-iPSCs were analyzed. Seven ADPKD-iPSC derived ECs, and seven ADPKD-iPSC derived SMCs were analyzed.
2016-08-04 | E-GEOD-74452 | biostudies-arrayexpress
Project description:Cardiovascular complications are the leading cause of death in autosomal dominant polycystic kidney disease (ADPKD), and intracranial aneurysm (ICA) causing subarachnoid hemorrhage is among the most serious complications. The diagnostic and therapeutic strategies for ICAs in ADPKD have not been fully established. We here generated induced pluripotent stem cells (iPSCs) from seven ADPKD patients, including four with ICAs. The vascular cells differentiated from ADPKD-iPSCs showed altered Ca2+ entry and gene expression profiles compared with those from control-iPSCs. We found that the expression level of a metalloenzyme gene, matrix metalloproteinase (MMP) 1, was specifically elevated in the iPSC-derived endothelia from ADPKD patients with ICAs. Furthermore, we confirmed a statistically significant correlation between the serum MMP1 levels and the development of ICAs in 354 ADPKD patients, indicating that the serum MMP1 levels may be a novel risk factor and become more beneficial when combined with other risk factors. These results suggest that cellular disease models with ADPKD-specific iPSCs can be used to study the disease mechanisms and to identify novel disease-related molecules or risk factors. The gene expression profiles of vascular endothelia and smooth muscle cells derived from control- and ADPKD-iPSCs were analyzed. Seven control-iPSC derived endothelial cells (ECs), seven ADPKD-iPSC derived ECs, ten control-iPSC derived vascular smooth muscle cells (SMCs), and seven ADPKD-iPSC derived SMCs were analyzed.
2016-08-04 | E-GEOD-74451 | biostudies-arrayexpress
Project description:Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a prevalent, life-threatening monogenetic disorder that affects millions worldwide. Currently, therapeutic options are limited and often associated with complications. To find more effective treatments, this study aimed to understand the molecular mechanisms driving cystogenesis in ADPKD. By analysing various epigenetic factors, we identified a set of master transcription factors that guided a core regulatory circuitry and remodeled chromatin accessibility in ADPKD. We further explored the role of immune cells, notably macrophages, in the disease’s progression using single-cell RNA sequencing. A subgroup of Lhfpl2+/Fat3+ macrophages, which reactivated the Hgf-Met-Nfkb1-Runx1 pathways, was found essential for cystic cell fate transition. Targeting the identified epigenetic regulators, H3K4me3 and TF Runx1, effectively halted disease progression in a mouse model. These findings may lead to innovative treatments for ADPKD in humans.
2024-10-10 | GSE244997 | GEO
Project description:Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a prevalent, life-threatening monogenetic disorder that affects millions worldwide. Currently, therapeutic options are limited and often associated with complications. To find more effective treatments, this study aimed to understand the molecular mechanisms driving cystogenesis in ADPKD. By analysing various epigenetic factors, we identified a set of master transcription factors that guided a core regulatory circuitry and remodeled chromatin accessibility in ADPKD. We further explored the role of immune cells, notably macrophages, in the disease’s progression using single-cell RNA sequencing. A subgroup of Lhfpl2+/Fat3+ macrophages, which reactivated the Hgf-Met-Nfkb1-Runx1 pathways, was found essential for cystic cell fate transition. Targeting the identified epigenetic regulators, H3K4me3 and TF Runx1, effectively halted disease progression in a mouse model. These findings may lead to innovative treatments for ADPKD in humans.
2024-10-10 | GSE244998 | GEO
Project description:Metabolic reprogramming is emerging as a key pathological contributor to the progression of autosomal dominant polycystic kidney disease (ADPKD), but the molecular mechanisms underlying dysregulated cellular metabolism in cystic cells remain elusive. Super-enhancers (SEs) are large clusters of transcriptional enhancers that drive robust expression of cell identity and disease genes. Here, we establish a prominent role for SEs in regulating metabolic gene expression and ADPKD progression. Characterization of cis-acting SE landscapes in cystic renal epithelial cells reveals extensive remodeling of SEs during cystogenesis. Gene ontology analysis indicates that SE-associated transcripts in the metabolic pathway category are most significantly enriched in cystic cells. Cystic cells are highly sensitive to the inhibition of cyclin-dependent kinase 7 (CDK7), a critical component of the trans-acting SE complex. THZ1, a specific CDK7 inhibitor, exerts a potent anti-cystogenesis effect in ADPKD cells and mouse models. Integrative analyses of transcriptomics and SE profiling identify AMP deaminase 3 (AMPD3) as a SE-driven metabolic gene. Up-regulation of AMPD3 in cystic cells results in reduced AMP level and decreased AMPK activity, while inhibition of AMPD3 suppresses cyst development in a zebrafish ADPKD model. In a cohort of ADPKD patients, CDK7 expression is frequently elevated, and its expression is significantly correlated with AMPD3 expression and disease severity. Taken together, our findings elucidate a mechanism by which SE controls metabolic gene transcription during cystogenesis, and identifies SE-driven metabolic reprogramming as a promising therapeutic target for ADPKD treatment.
2020-05-16 | GSE141279 | GEO
Project description:ADPKD is the most common genetic renal disease, leading to renal failure in the vast majority of affected individuals. Standard therapy consists of blood pressure control and salt restriction. Tolvaptan further delays renal failure but side effects prevent its widespread use. Novel therapeutic approaches are needed. Recent evidence has identified inflammation as an important driver of ADPKD. Here we show a strong inflammatory signature in transcriptomes of early ADPKD in the mouse. IL1β and IL18, effectors of inflammasome activation, are among the top upregulated transcripts. Inflammasomes act as part of the innate immune response to danger signals, including crystals. Induction of calcium oxalate crystals through dietary intervention in Pkd1 mutant mice aggravated the cystic phenotype. Treatment of Pkd1 mutant mice with the inflammasome inhibitor MCC950 significantly ameliorated the ADPKD phenotype. Analogous results were obtained through genetic silencing of the essential inflammasome component Asc in ADPKD mice. Interference with inflammasome activation in the ADPKD animals resulted in better renal function and decreased IL18 excretion in the urine. These findings identify inflammasome inhibition as a promising concept for the treatment of ADPKD.
2025-11-03 | GSE273186 | GEO
Project description:Transcription factors (TFs) play crucial roles in kidney development and disease by recognizing specific DNA sequences to control gene expression programs. The kidney’s cellular heterogeneity poses substantial challenges to identifying the genomic binding sites and direct target genes of TFs in vivo. We apply the CUT&RUN (cleavage under targets and release using nuclease) technique, together with transcriptomic analysis, to identify cAMP-response element-binding protein (CREB) target genes in cystic epithelial cells of autosomal dominant polycystic kidney disease (ADPKD). Our results reveal that CREB binds to and activates ribosomal biogenesis genes, and that inhibition of CREB retards cyst growth in ADPKD mouse models. Our findings demonstrate that CUT&RUN is a powerful method for genome-scale profiling and identifying direct targets of TFs from small numbers of specific kidney cells.
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Project description:Metabolic reprogramming is emerging as a key pathological contributor to the progression of autosomal dominant polycystic kidney disease (ADPKD), but the molecular mechanisms underlying dysregulated cellular metabolism in cystic cells remain elusive. Super-enhancers (SEs) are large clusters of transcriptional enhancers that drive robust expression of cell identity and disease genes. Here, we establish a prominent role for SEs in regulating metabolic gene expression and ADPKD progression. Characterization of cis-acting SE landscapes in cystic renal epithelial cells reveals extensive remodeling of SEs during cystogenesis. Gene ontology analysis indicates that SE-associated transcripts in the metabolic pathway category are most significantly enriched in cystic cells. Cystic cells are highly sensitive to the inhibition of cyclin-dependent kinase 7 (CDK7), a critical component of the trans-acting SE complex. THZ1, a specific CDK7 inhibitor, exerts a potent anti-cystogenesis effect in ADPKD cells and mouse models. Integrative analyses of transcriptomics and SE profiling identify AMP deaminase 3 (AMPD3) as a SE-driven metabolic gene. Up-regulation of AMPD3 in cystic cells results in reduced AMP level and decreased AMPK activity, while inhibition of AMPD3 suppresses cyst development in a zebrafish ADPKD model. In a cohort of ADPKD patients, CDK7 expression is frequently elevated, and its expression is significantly correlated with AMPD3 expression and disease severity. Taken together, our findings elucidate a mechanism by which SE controls metabolic gene transcription during cystogenesis, and identifies SE-driven metabolic reprogramming as a promising therapeutic target for ADPKD treatment.
2020-05-16 | GSE146714 | GEO
Project description:Metabolic reprogramming is emerging as a key pathological contributor to the progression of autosomal dominant polycystic kidney disease (ADPKD), but the molecular mechanisms underlying dysregulated cellular metabolism in cystic cells remain elusive. Super-enhancers (SEs) are large clusters of transcriptional enhancers that drive robust expression of cell identity and disease genes. Here, we establish a prominent role for SEs in regulating metabolic gene expression and ADPKD progression. Characterization of cis-acting SE landscapes in cystic renal epithelial cells reveals extensive remodeling of SEs during cystogenesis. Gene ontology analysis indicates that SE-associated transcripts in the metabolic pathway category are most significantly enriched in cystic cells. Cystic cells are highly sensitive to the inhibition of cyclin-dependent kinase 7 (CDK7), a critical component of the trans-acting SE complex. THZ1, a specific CDK7 inhibitor, exerts a potent anti-cystogenesis effect in ADPKD cells and mouse models. Integrative analyses of transcriptomics and SE profiling identify AMP deaminase 3 (AMPD3) as a SE-driven metabolic gene. Up-regulation of AMPD3 in cystic cells results in reduced AMP level and decreased AMPK activity, while inhibition of AMPD3 suppresses cyst development in a zebrafish ADPKD model. In a cohort of ADPKD patients, CDK7 expression is frequently elevated, and its expression is significantly correlated with AMPD3 expression and disease severity. Taken together, our findings elucidate a mechanism by which SE controls metabolic gene transcription during cystogenesis, and identifies SE-driven metabolic reprogramming as a promising therapeutic target for ADPKD treatment.
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Project description:Cardiovascular complications are the leading cause of death in autosomal dominant polycystic kidney disease (ADPKD), and intracranial aneurysm (ICA) causing subarachnoid hemorrhage is among the most serious complications. The diagnostic and therapeutic strategies for ICAs in ADPKD have not been fully established. We here generated induced pluripotent stem cells (iPSCs) from seven ADPKD patients, including four with ICAs. The vascular cells differentiated from ADPKD-iPSCs showed altered Ca2+ entry and gene expression profiles compared with those from control-iPSCs. We found that the expression level of a metalloenzyme gene, matrix metalloproteinase (MMP) 1, was specifically elevated in the iPSC-derived endothelia from ADPKD patients with ICAs. Furthermore, we confirmed a statistically significant correlation between the serum MMP1 levels and the development of ICAs in 354 ADPKD patients, indicating that the serum MMP1 levels may be a novel risk factor and become more beneficial when combined with other risk factors. These results suggest that cellular disease models with ADPKD-specific iPSCs can be used to study the disease mechanisms and to identify novel disease-related molecules or risk factors.
2016-08-04 | GSE74451 | GEO