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GSE101308
Homo sapiens
7 Downloadable Samples
Affymetrix Human Gene 2.0 ST Array (hugene20st)
Description
Computational identification of gene expression pathways in cysts alongside tubular organoids
Publication Title
Organoid cystogenesis reveals a critical role of microenvironment in human polycystic kidney disease.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 30 Downloadable Samples
Illumina HiSeq 2500
Description
The endothelium first forms in the blood islands in the extra-embryonic yolk sac and then throughout the embryo to establish circulatory networks that further acquire organ-specific properties during development to support diverse organ functions. Here, we investigated the properties of endothelial cells (ECs), isolated from four human major organsthe heart, lung, liver, and kidneys in individual fetal tissues at three months'' gestation, at gene expression, and at cellular function levels. We showed that organ-specific ECs have distinct expression patterns of gene clusters, which support their specific organ development and functions. These ECs displayed distinct barrier properties, angiogenic potential, and metabolic rate and support specific organ functions. Our findings showed the link between human EC heterogeneity and organ development and can be exploited therapeutically to contribute in organ regeneration, disease modeling, as well as guiding differentiation of tissue-specific ECs from human pluripotent stem cells. Overall design: We examined the human fetal organ sets from three donors, constituting three biological replicates at 3 months'' gestation (100-125 days). At this stage, all four major organs of interest - the heart, kidney, lung, and liver - have an established microvascular supply and exhibit organ-specific function. The heart beats at 120-160 bpm and is approximately 2 cm, the lungs have developed the entire air-conducting bronchial tree up to 20 generations with respiratory ducts and start to form barriers between alveoli and blood vessels, the liver is the major site of blood cell production and has also started to produce bile, and the kidneys have established nephrons and start to produce urine.
Publication Title
Human Organ-Specific Endothelial Cell Heterogeneity.
Sample Metadata Fields
Specimen part, Subject
View Samples- Homo sapiens
- 6 Downloadable Samples
- Illumina HumanHT-12 V4.0 expression beadchip
Description
Kidney peritubular capillaries are particularly susceptible to rarefaction and regeneration-limited after exposure to toxins or injuries. Studying these kidney microvessels remain challenging, primarily resulting from difficulties imaging in vivo, as well as isolating and culturing kidney microvascular cells in vitro, in particular in a three-dimensional (3D) microenvironment with proper hemodynamics. Here, we developed methods to isolate, purify, and characterize human kidney peritubular microvascular endothelial cells (hKMECs), and reconstituted a 3D kidney microvasculature in collagen matrix. Compared to other endothelial cells, isolated hKMECs are very sensitive to VEGF for survival and growth, and have a high vasculogenic but low angiogenic potential. Under flow, they formed a fenestrated endothelium with a comprehensive permeability barrier. When exposed to calcineurin inhibitors, hKMECs formed microvessels displayed cell retraction, broken fenestrae, and swollen endothelium, which led to a thrombogenic luminal wall and erythrocytes extravasations into the subendothelial space. Our study recapitulated the human kidney microvascular structure and function, and shed lights on potential mechanistic studies of kidney specific injuries and diseases.
Publication Title
A Novel Three-Dimensional Human Peritubular Microvascular System.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 18 Downloadable Samples
- Illumina HiSeq 2000
Description
Chronic kidney disease (CKD) is the gradual, asymptomatic loss of kidney function and current tests only identify it when significant loss has already happened. Using RNA sequencing in a mouse model of folic acid (FA) induced nephropathy, here we report the identification of 10 genes that track kidney fibrosis development, the common pathological finding in CKD patients. The gene expression of all 10 candidates was confirmed to be significantly high (~ 10-150 fold) in three well-established and mechanistically distinct mouse models of kidney fibrosis. Protein expression was also high in the FA model as well as patients with biopsy-proven kidney fibrosis. The specificity of these 10 candidates for kidney fibrosis was demonstrated by showing a very modest (~ 2-5 fold) increase in the mouse models of acute kidney injury as well as following liver fibrosis in mice and humans. Using targeted selected reaction monitoring mass spectrometry (SRM-MS) we found that 3 out of 10, cadherin 11 (CDH11), mannose receptor C1 (MRC1), phospholipid transfer protein (PLTP), are detectable in human urine. Furthermore, the levels of CDH11 and MRC1 are able to distinguish patients with chronic kidney disease from healthy individuals (n = 78, p<0.01). In summary, we report the identification of CDH11 and MRC1 as novel non-invasive biomarkers of CKD. Overall design: mRNA sequencing of mouse kidney before and at various time points (1,2,3,7 & 14 days) after intraperitoneal treatment with folic acid.
Publication Title
RNA Sequencing Identifies Novel Translational Biomarkers of Kidney Fibrosis.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 73 Downloadable Samples
- NextSeq 500
Description
Drug-induced kidney injury, largely caused by proximal tubular intoxicants, limits development and clinical use of new and approved drugs. Assessing preclinical nephrotoxicity relies on animal models that are frequently insensitive, and thus, novel techniques, including human microphysiological systems, or “organs on chips,” are proposed to accelerate drug development and predict safety. Polymyxins are potent antibiotics against multidrug-resistant microorganisms; yet clinical use remains restricted because of high risk of nephrotoxicity and limited understanding of toxicological mechanisms. To mitigate risks, structural analogs of polymyxins (NAB739 and NAB741) are currently in clinical development. Using a microphysiological system to model human kidney proximal tubule, we exposed cells to polymyxin B (PMB) and observed significant increases of injury signals, including kidney injury molecule-1 KIM-1and a panel of injury-associated miRNAs (each P < 0.001). Surprisingly, transcriptional profiling identified cholesterol biosynthesis as the primary cellular pathway induced by PMB (P = 1.2 ×10–16), and effluent cholesterol concentrations were significantly increased after exposure (P < 0.01). Additionally, we observed no upregulation of the nuclear factor (erythroid derived-2)–like 2 pathway despite this being a common pathway upregulated in response to proximal tubule toxicants. In contrast with PMB exposure, minimal changes in gene expression, injury biomarkers, and cholesterol concentrations were observed in response to NAB739 and NAB741. Our findings demonstrate the preclinical safety of NAB739 and NAB741 and reveal cholesterol biosynthesis as the novel (to our knowledge) pathway for PMB- induced injury. To our knowledge, this is the first demonstration of a human-on-chip platform used for simultaneous safety testing of new chemical entities and defining unique toxicological pathway responses of an FDA-approved molecule. Overall design: Cells from six donors were seeded into a total of 74 kidney chips, and effluents of kidney MPS were exposed for 48 hours of treatments
Publication Title
Human kidney on a chip assessment of polymyxin antibiotic nephrotoxicity.
Sample Metadata Fields
Specimen part, Treatment, Subject
View Samples- Mus musculus, Rattus norvegicus
- 100 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
-chloroprene (2-chloro-1,3-butadiene), a monomer used in the production of neoprene elastomers, is of regulatory interest due to the production of multi-organ tumors in mouse and rat cancer bioassays. A significant increase in female mouse lung tumors was observed at the lowest exposure concentration of 12.8 ppm while a small, but not statistically significant, increase was observed in female rats only at the highest exposure concentration of 80 ppm. The metabolism of chloroprene results in the generation of reactive epoxides and the rate of overall chloroprene metabolism is highly species dependent. To identify potential key events in the mode-of-action of chloroprene lung tumorigenesis, dose response and time course gene expression microarray measurements were made in the lungs of female mice and female rats. The gene expression changes were analyzed using both a traditional analysis of variance approach followed by pathway enrichment analysis and a pathway-based benchmark dose (BMD) analysis approach. Pathways related to glutathione biosynthesis and metabolism were the primary pathways consistent with cross-species differences in tumor incidence and transcriptional BMD values for the pathway were more similar to differences in tumor response than were estimated target tissue dose surrogates based on the total amount of chloroprene metabolized per unit mass of lung tissue per day. The closer correspondence of the transcriptional changes with the tumor response are likely due to their reflection of the overall balance between metabolic activation and detoxication reactions whereas the current tissue dose surrogate reflects only oxidative metabolism.
Publication Title
Cross-species transcriptomic analysis of mouse and rat lung exposed to chloroprene.
Sample Metadata Fields
Sex, Age, Specimen part, Subject
View Samples- Mus musculus
- 11 Downloadable Samples
- Illumina HiSeq 2000
Description
Purpose: MicroRNA-21 contributes to the pathogenesis of fibrogenic diseases in multiple organs including the kidney. To evaluate the therapeutic utility of antimiR-21 oligonucleotides in chronic kidney disease, we silenced miR-21 in mice that develop Alport Nephropathy due to a defect in the Col4a3 gene. The goals of this study to assess the effect of inhibiting miR-21 in the Col4a3-/- Alport Syndrome mouse model at 5.5 weeks of age. Methods: Col4a3-/-, Col4a3+/-, and Col4a3+/+ mice in the 129X1/SvJ genetic background were obtained. Mice received anti–miR-21 (25 mg/kg) or control anti-miR (25mg/kg) in phosphate-buffered saline (PBS) by inter-scapular subcutaneous injection twice per week. In some experiments mice received a range of doses from 12.5mg/kg once a week to 50mg/kg once a week. Anti–miR-21 is a high-affinity oligonucleotide complementary to the active site of miR-21. Mice received injections starting at 24 days (3.5 weeks) after birth and ending at 5, 7, 9 or 16 weeks after birth depending on the study objectives. Total RNA from kidney tissue was extracted as per manufacturer’s instructions (miREASY kit, Qiagen). RNA quality was assessed using BioAnalyzer (Agilent). mRNA expression profiles were determined using next-generation sequencing (NGS) on the Illumina HiSeq 2000 platform producing 50bp paired-end reads. Bowtie/TopHat suites were used to align the reads to mouse genome or transcriptome and RSEM were used to quantify gene abundances. Gene level counts were then normalized with the R/Bioconductor package limma using the voom/variance stabilization method. Results: Anti-miR-21 enhanced PPARa/RXR activity and associated downstream signaling pathways in glomerular, tubular and interstitial cells, enhanced mitochondrial function, which reduced mitochondrial ROS production and preserved tubular cell functions. In addition, inhibition of miR-21 reduced fibrogenic and inflammatory signaling in glomerular and interstitial cells, likely as a consequence of enhanced PPARa/RXR activity and mitochondrial function. Inhibition of miR-21 represents a novel therapeutic strategy for chronic kidney diseases including Alport Nephropathy. Overall design: Whole kidney mRNA profiles of Col4a3+/- (triplicate) and Col4a3-/- (quadruplicates) mice treated with either PBS or antimiR-21, ending at 5.5 weeks of age, were generated by Next Generation Sequencing using Illumina HiSeq 2000
Publication Title
Anti-microRNA-21 oligonucleotides prevent Alport nephropathy progression by stimulating metabolic pathways.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 8 Downloadable Samples
- Illumina HiSeq 2500
Description
We generated primary cultures from renal cell carcinoma and matched normal primary kidney cortex tubule cell cultures from 3 patients. Early passage cultures of these two cell types were subjected to chromatin accessibility profiling (DNase-seq) and gene expression profiling (RNA-seq). Studying these paired and patient-matched controlled data sets will shed light on the epigenomic changes that underlie transformation of kidney tubules into malignant cancers. Overall design: Paired DNase-seq and RNA-seq data sets from 2 different primary human kidney cell types (normal and cancer) Note from submitter: The HIM23 samples have a more narrow consent and their raw data will be submitted to dbGaP.
Publication Title
Integrated epigenomic profiling reveals endogenous retrovirus reactivation in renal cell carcinoma.
Sample Metadata Fields
Sex, Age, Cell line, Subject
View Samples- Homo sapiens
- 51 Downloadable Samples
- Affymetrix Human Genome U133A 2.0 Array (hgu133a2)
Description
The aim of this data set is to measure the effect of rofecoxib and celecoxib on the transcription profile in an in vitro inflammation model. Transcription profiling was carried out using Affymetrix HG U-133A v2 microarrays.
Publication Title
Understanding multicellular function and disease with human tissue-specific networks.
Sample Metadata Fields
Sex, Specimen part, Race, Time
View Samples- Mus musculus
- 53 Downloadable Samples
- Illumina HiSeq 2000
Description
A central challenge in pharmaceutical research is to investigate genetic variation in response to drugs. The Collaborative Cross (CC) mouse reference population is a promising model for pharmacogenomic studies because of its large amount of genetic variation, genetic reproducibility, and dense recombination sites. While the CC lines are phenotypically diverse, their genetic diversity in drug disposition processes, such as detoxification reactions, is still largely uncharacterized. Here we systematically measured RNA-sequencing expression profiles from livers of 29 CC lines under baseline conditions. We then leveraged a reference collection of metabolic biotransformation pathways to map potential relations between drugs and their underlying expression quantitative trait loci (eQTLs). By applying this approach on proximal eQTLs, including eQTLs acting on the overall expression of genes and on the expression of particular transcript isoforms, we were able to construct the organization of hepatic eQTL-drug connectivity across the CC population. The analysis revealed a substantial impact of genetic variation acting on drug biotransformation, allowed mapping of potential joint genetic effects in the context of individual drugs, and demonstrated crosstalk between drug metabolism and lipid metabolism. Our findings provide a resource for investigating drug disposition in the CC strains, and offer a new paradigm for integrating biotransformation reactions to corresponding variations in DNA sequences. Overall design: This dataset includes RNA-Seq data of mRNA that were extracted from the liver of 55 male mice. The 55 mice belong to 29 different collaborative cross strains. The number of individual mice per strains is 3 for 3 strains, 2 for 16 strains, and 1 for 8 strains. All the mice are naïve without any special treatment.
Publication Title
Dissecting the Effect of Genetic Variation on the Hepatic Expression of Drug Disposition Genes across the Collaborative Cross Mouse Strains.
Sample Metadata Fields
Specimen part, Cell line, Subject
View Samples