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Title: The molecular basis of the renal and vascular consequences of Uremia      
dateReleased:
06-30-2013
description:
Background. Chronic renal failure is characterized by progressive renal scarring and accelerated cardiovascular disease. In animal models, this is thought to be due to non-dialyzable uremic toxins – small, protein-bound molecules normally secreted via Organic Anion Transporters (OATs) in the proximal renal tubule,rather than filtered at the glomerulus. The best studied of these is indoxyl sulfate (IS). Methods. We examined global gene expression responses in cultured normal human renal tubular cells incubated with control plasma (n=5) or pre- and post-dialysis uremic plasma (n=10). Results. GeneSpring analysis of microarrays revealed significantly altered expression of 2016 genes. The expression of 537 genes “normalized” in post-dialysis plasma, suggesting removal of “low molecular weight uremic toxins” by dialysis. The expression of the majority of dysregulated genes (1479) was not normalized in post-dialysis plasma. These likely represent the effects of substances not effectively removed by dialysis (“protein-bound uremic toxins”). Addition of indoxyl sulfateto control plasma simulated most effects (81.1%) of uremic plasma, while the addition of probenecid, an OAT inhibitor, to uremic plasma reversed most changes in gene expression. Analysis of molecular programs with the Gene Set Enrichment Analysis and the DAVID database revealed patterns common to indoxyl sulfate-treated control plasma, pre-dialysis, and post-dialysis uremic plasma. These included increased cell cycle, pro-inflammatory, and pro-fibrotic molecular programs, particularly genes in the TGF-β pathway. Conclusion: These findings provide insight into the role of non-dialyzable, protein-bound uremic toxins in the pathogenesis of renal scarring and uremic vasculopathy. The GSEA patterns confirm that inflammatory and fibrotic programs are active. Transcriptomic remodeling in response to external stimulus RNA from non-immortalized cultured renal cortical cells incubated with plasma samples from 5 controls, 10 uremics pre-dialysis, 10 uremics post-dialysis, 5 controls with indoxyl sulfate added, 5 uremics pre-dialysis with probenecid added, 5 uremics post-dialysis with indoxyl sulfate added
privacy:
not applicable
aggregation:
instance of dataset
ID:
E-GEOD-45709
refinement:
raw
alternateIdentifiers:
45709
keywords:
functional genomics
dateModified:
07-09-2013
availability:
available
types:
gene expression
name:
Homo sapiens
ID:
A-AFFY-141
name:
Affymetrix GeneChip Human Gene 1.0 ST Array [HuGene-1_0-st-v1]
accessURL: https://www.ebi.ac.uk/arrayexpress/files/E-GEOD-45709/E-GEOD-45709.raw.1.zip
storedIn:
ArrayExpress
qualifier:
gzip compressed
format:
TXT
accessType:
download
authentication:
none
authorization:
none
accessURL: https://www.ebi.ac.uk/arrayexpress/files/E-GEOD-45709/E-GEOD-45709.processed.1.zip
storedIn:
ArrayExpress
qualifier:
gzip compressed
format:
TXT
accessType:
download
authentication:
none
authorization:
none
accessURL: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE45709
storedIn:
Gene Expression Omnibus
qualifier:
not compressed
format:
HTML
accessType:
landing page
primary:
true
authentication:
none
authorization:
none
abbreviation:
EBI
homePage: http://www.ebi.ac.uk/
ID:
SCR:004727
name:
European Bioinformatics Institute
homePage: https://www.ebi.ac.uk/arrayexpress/
ID:
SCR:002964
name:
ArrayExpress
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