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| Status |
Public on Oct 01, 2017 |
| Title |
Progressive kidney disease is suppressed by a small molecule inhibitor of TRPC5 |
| Organism |
Rattus norvegicus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Purpose: To characterize the transcriptional responses to TRPC5 inhibition in vivo, we compared gene expression profiles (RNASeq) in isolated glomeruli from wild type (WT) rats, AC1903-treated AT1R transgenic (Tg) rats in the advanced cohort and vehicle-treated, age-matched AT1R controls.
Methods: Glomerular mRNA profiles of WT rats, AC1903-treated AT1R transgenic (Tg) rats in the advanced cohort and vehicle-treated, age-matched AT1R controls were generated by deep sequencing using Illumina. Sequenced reads were mapped by STAR and quanitifed using RSEM. Differential expression analysis and Gene Ontology term enrichment analysis was performed.
Results: We identified 541 differentially expressed genes in AT1R Tg rats compared to WT controls. Interestingly, Gene Ontology (GO) term enrichment analysis revealed ROS-related and ion (cation) channel and transporter activity gene signatures, in line with the hypothesis that Rac1-mediated ROS generation and TRPC5 Ca2+ (cation) mediated signaling lead to disease progression. After treatment with AC1903, 42 genes were differentially expressed in AC1903-treated versus vehicle-treated AT1R Tg rats. This smaller number of genes is consistent with the notion that AC1903 targets a specific pathway triggered by TRPC5 activity to confer its therapeutic advantage. GO term enrichment analysis revealed cell adhesion and integrin signaling gene sets, consistent with our observations in vivo that AC1903 protects podocytes from attenuations, detachment and loss.
Conclusions: In short, the in vivo gene expression profiles support a Rac1-TRPC5 disease-promoting pathway in proteinuric kidney disease that is reversed by treatment with AC1903.
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| Overall design |
Glomerular mRNA profiles of WT and AC1903-treated AT1R Tg rats in the advanced cohort and vehicle-treated, age-matched AT1R controls were generated by deep sequencing using Illumina HiSeq 2000
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| Contributor(s) |
Clark AR, Greka A |
| Citation(s) |
29217578 |
| Submission date |
Aug 23, 2017 |
| Last update date |
Jun 18, 2019 |
| Contact name |
Abbe Rose Clark |
| Organization name |
Harvard, Brigham and Women's Hospital
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| Street address |
4 Blackfan Circle, HIM 534
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| City |
Boston |
| State/province |
Massachusetts |
| ZIP/Postal code |
02115 |
| Country |
USA |
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| Platforms (1) |
| GPL14844 |
Illumina HiSeq 2000 (Rattus norvegicus) |
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| Samples (6)
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| Relations |
| BioProject |
PRJNA399880 |
| SRA |
SRP116102 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE103020_Differential_expression_analysis_AC1903vVeh.txt.gz |
175.3 Kb |
(ftp)(http) |
TXT |
| GSE103020_Differential_expression_analysis_AT1RTgvWT.txt.gz |
215.3 Kb |
(ftp)(http) |
TXT |
| GSE103020_genes.results.txt.gz |
257.6 Kb |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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