Similar Datasets
Project description:To elucidate the molecular pathways that modulate renal cyst growth in autosomal dominant polycystic kidney disease (ADPKD) Keywords: Disease state analysis We performed global gene profiling on renal cysts of different size (small cysts: less than 1 ml, n=5; medium cysts: between 10-25 ml, n=5; large cysts: greater than 50 ml, n=3) and minimally cystic tissue (MCT, n=5) from five PKD1 polycystic kidneys. Additionally, non-cancerous renal cortical tissue from three nephrectomized kidneys with isolated renal cell carcinoma was used as normal control tissue (n=3). This dataset is part of the TransQST collection.
2009-08-14 | E-GEOD-7869 | biostudies-arrayexpress
Project description:To elucidate the molecular pathways that modulate renal cyst growth in autosomal dominant polycystic kidney disease (ADPKD) Keywords: Disease state analysis
2009-08-14 | GSE7869 | GEO
Project description:Background: Autosomal dominant polycystic kidney disease (ADPKD) affects more than 12 million people worldwide. Mutations in PKD1 and PKD2 cause cyst formation through unknown mechanisms. To unravel the pathogenic mechanisms in ADPKD, multiple studies have investigated transcriptional mis-regulation in cystic kidneys from patients and mouse models, and numerous dysregulated genes and pathways have been described. Yet, the concordance between studies has been rather limited. Furthermore, the cellular and genetic diversity in cystic kidneys has hampered the identification of mis-expressed genes in kidney epithelial cells with homozygous PKD mutations, which are critical to identify polycystin-dependent pathways. Methods: Autosomal dominant polycystic kidney disease (ADPKD) affects more than 12 million people worldwide. Mutations in PKD1 and PKD2 cause cyst formation through unknown mechanisms. To unravel the pathogenic mechanisms in ADPKD, multiple studies have investigated transcriptional mis-regulation in cystic kidneys from patients and mouse models, and numerous dysregulated genes and pathways have been described. Yet, the concordance between studies has been rather limited. Furthermore, the cellular and genetic diversity in cystic kidneys has hampered the identification of mis-expressed genes in kidney epithelial cells with homozygous PKD mutations, which are critical to identify polycystin-dependent pathways. Results: Autosomal dominant polycystic kidney disease (ADPKD) affects more than 12 million people worldwide. Mutations in PKD1 and PKD2 cause cyst formation through unknown mechanisms. To unravel the pathogenic mechanisms in ADPKD, multiple studies have investigated transcriptional mis-regulation in cystic kidneys from patients and mouse models, and numerous dysregulated genes and pathways have been described. Yet, the concordance between studies has been rather limited. Furthermore, the cellular and genetic diversity in cystic kidneys has hampered the identification of mis-expressed genes in kidney epithelial cells with homozygous PKD mutations, which are critical to identify polycystin-dependent pathways. Conclusions: Autosomal dominant polycystic kidney disease (ADPKD) affects more than 12 million people worldwide. Mutations in PKD1 and PKD2 cause cyst formation through unknown mechanisms. To unravel the pathogenic mechanisms in ADPKD, multiple studies have investigated transcriptional mis-regulation in cystic kidneys from patients and mouse models, and numerous dysregulated genes and pathways have been described. Yet, the concordance between studies has been rather limited. Furthermore, the cellular and genetic diversity in cystic kidneys has hampered the identification of mis-expressed genes in kidney epithelial cells with homozygous PKD mutations, which are critical to identify polycystin-dependent pathways.
2021-07-15 | GSE179947 | GEO
Project description:Alteration of DNA methylation leads to diverse diseases, and the dynamic changes of DNA methylation (DNAm) on sets of CpG dinucleotides in mammalian genomes, named as “DNAm age” and “epigenetic clocks” that can predict chronological age. However, whether and how dysregulation of DNA methylation promotes cyst progression and epigenetic age acceleration in ADPKD remains elusive. In this study, we show that DNA methyltransferase 1 (DNMT1) is upregulated in cystic renal epithelial cells and tissues, and that knockout of Dnmt1 and targeting DNMT1 with hydralazine, a safe demethylating agent, delays cyst growth in Pkd1 mutant kidneys and extends life span of Pkd1 conditional knockout mice. With methyl-CpG binding domain (MBD) protein-enriched genome sequencing (MBD-seq), DNMT1 chromatin immunoprecipitation (ChIP)-sequencing and RNA-sequencing analysis, we identify two novel DNMT1 targets, PTPRM and PTPN22 (members of the protein tyrosine phosphatase family), which function as mediators of DNMT1 and the phosphorylation and activation of PKD associated signaling pathways, including ERK, mTOR and STAT3. With whole genome bisulfide sequencing (WGBS) in ADPKD kidneys versus normal individuals, we found that the methylation of epigenetic clock associated genes were dysregulated, supporting that epigenetic age was accelerated in ADPKD kidneys. We further identify four epigenetic clock associated genes, including Hsd17b14, Mbnl1, Rassf5 and Plk2. The diverse biological roles of these four genes suggest that their methylation status may not only predict epigenetic age acceleration but also contribute to disease progression in ADPKD.
2024-06-11 | GSE257535 | GEO
Project description:Autosomal Dominant Polycystic Kidney Disease (ADPKD; MIM ID’s 173900, 601313, 613095) leads to end stage kidney disease, caused by mutations in PKD1 or PKD2. Inactivation of Pkd1 before or after P13 in mice results in distinct early- or late-onset disease. Using a mouse model of ADPKD carrying floxed Pkd1 alleles disrupted using a tamoxifen-inducible Cre recombinase, transcriptomics and metabolomics were applied to follow disease progression in animals induced before P10. Network analysis suggests that Pkd1-cystogenesis does not cause developmental arrest and occurs in the context of gene networks similar to those that regulate/maintain normal kidney morphology/function. These analyses also predict metabolic pathways, notably those controlled by HNF4α, are key elements in postnatal kidney maturation and early steps of cyst formation. To test this hypothesis, metabolic networks were altered by inactivating Hnf4a and Pkd1. The Pkd1/Hnf4a double knock-out have significantly more cystic kidneys thus indicating that modulating metabolic pathways might be an effective therapeutic approach.
2012-11-29 | GSE32586 | GEO
Project description:Autosomal Dominant Polycystic Kidney Disease (ADPKD; MIM ID’s 173900, 601313, 613095) leads to end stage kidney disease, caused by mutations in PKD1 or PKD2. Inactivation of Pkd1 before or after P13 in mice results in distinct early- or late-onset disease. Using a mouse model of ADPKD carrying floxed Pkd1 alleles disrupted using a tamoxifen-inducible Cre recombinase, transcriptomics and metabolomics were applied to follow disease progression in animals induced before P10. Network analysis suggests that Pkd1-cystogenesis does not cause developmental arrest and occurs in the context of gene networks similar to those that regulate/maintain normal kidney morphology/function. These analyses also predict metabolic pathways, notably those controlled by HNF4α, are key elements in postnatal kidney maturation and early steps of cyst formation. To test this hypothesis, metabolic networks were altered by inactivating Hnf4a and Pkd1. The Pkd1/Hnf4a double knock-out have significantly more cystic kidneys thus indicating that modulating metabolic pathways might be an effective therapeutic approach. We crossed fifth-generation C57/BL6 Pkd1cond mice to fifth-generation C57/BL6 tamoxifen-Cre (B6.Cg-Tg(Cre/Esr1)5Amc/J mice (stock 004682), Jackson Laboratories) and C57/BL6 congenic B6.129S4-Gt(ROSA)26Sortm1Sor/J (stock 003474, Jackson Laboratories) to produce Pkd1 conditional mice with TamCre (mutant) or without TamCre (control). We induced Cre recombinase activity in mice < 10 days of age by intraperitoneally injecting nursing mothers with tamoxifen (10 mg/40 g) , and harvested kidney samples of control and mutant (34 and 36 animals, respectively) between the ages of 11 and 24 days. Postprocessed files (expression p value<0.05; quantile normalized; merged and corrected for batch-effect using COMBAT) linked below as supplementary files.
2012-11-29 | E-GEOD-32586 | biostudies-arrayexpress
Project description:Human pluripotent stem cell-derived organoids are models for human development and disease. We report a modified human kidney organoid system that generates thousands of similar kidney organoids, each consisting of 1 to 2 nephron-like structures. Single-cell transcriptomic profiling and immunofluorescence validation highlighted patterned nephron-like structures, utilizing similar pathways, with distinct morphogenesis, to human nephrogenesis. To examine this platform for therapeutic screening, the polycystic kidney disease genes PKD1 and PKD2 were inactivated by gene-editing. PKD1 and PKD2 mutant models exhibited efficient and reproducible cyst formation. Cystic outgrowths could be propagated for months to centimeter-sized cysts. To shed new light on cystogenesis, 247 protein kinase inhibitors (PKI) were screened in a live imaging assay identifying novel compounds blocking cyst formation but not overall organoid growth. Scaling and further development of the organoid platform will enable a broader capability for kidney disease modeling and high-throughput drug screens.
2022-06-23 | GSE164564 | GEO
Project description:Autosomal dominant polycystic kidney disease (ADPKD) is a debilitating disease that is characterized by the accumulation of numerous fluid-filled cysts in the kidney. ADPKD is primarily caused by mutations in two genes, PKD1 and PKD2. Long noncoding RNAs (lncRNA) – defined by a length >200 nucleotides and absence of a long open reading frame – have recently emerged as epigenetic regulators of development and disease; however, their involvement in PKD has not been explored previously. Here, we performed deep RNA sequencing to identify lncRNAs that are dysregulated in two orthologous mouse models of ADPKD (kidney-specific Pkd1 and Pkd2 mutant mice). We identified a kidney- specific, evolutionarily-conserved lncRNA called Hoxb3os that was downregulated in cystic kidneys from Pkd1 and Pkd2 mutant mice. The human ortholog HOXB3-AS1 was downregulated in cystic kidneys from ADPKD patients. Hoxb3os was highly expressed in renal tubules in adult wild- type mice, whereas its expression was lost in the cyst epithelium of mutant mice. To investigate the function of Hoxb3os, we utilized CRISR/Cas9 to knockout its expression in mIMCD3 cells. Deletion of Hoxb3os resulted in increased phosphorylation of mTOR and its downstream targets, including p70 S6 kinase, ribosomal protein S6, and the translation repressor 4E-BP1. Consistent with activation of mTORC1 signaling, Hoxb3os mutant cells displayed increased mitochondrial respiration. The Hoxb3os mutant phenotype was partially rescued upon re- expression of Hoxb3os in knockout cells. These findings identify Hoxb3os as a novel lncRNA that is downregulated in ADPKD and regulates mTOR signaling and mitochondrial respiration.
2018-04-30 | GSE108864 | GEO
Project description:ADPKD (Autosomal dominant polycystic kidney disease) is the most common inherited disorders and is characterized by growth of numerous cysts filled with fluid in the kidneys. Ultimately, it leads to kidney failure. The mutations of PKD1 and PKD2 account for approximately 85 and 15 percent of ADPKD, respectively. However, the mechanisms related to genetic mutation of PKD1 and PKD2 are still unclear. To investigate altered gene expression levels, Affymetrix microarray was performed using the kidney tissue from normal and ADPKD patients.
2012-02-16 | GSE35831 | GEO
Project description:ADPKD (Autosomal dominant polycystic kidney disease) is the most common inherited disorders and is characterized by growth of numerous cysts filled with fluid in the kidneys. Ultimately, it leads to kidney failure. The mutations of PKD1 and PKD2 account for approximately 85 and 15 percent of ADPKD, respectively. However, the mechanisms related to genetic mutation of PKD1 and PKD2 are still unclear. To investigate altered gene expression levels, Affymetrix microarray was performed using the kidney tissue from normal and ADPKD patients. Total RNAs were isolated from kidney of human normal (49 years old/ male) and ADPKD patients (62 years old/ male, 67 years old/ male) using NucleoSpin® RNA Kit (MACHEREY-NAGEL) according to the manufacturer’s instructions. We used tha Affymetrix GeneChip Human Gene 1.0 ST Array. Per RNA sample, 300 ng was used as the input into the Affymetrix procedure as recommended by the manufacturer's protocol.
2012-02-16 | E-GEOD-35831 | biostudies-arrayexpress