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Status |
Public on Dec 02, 2019 |
Title |
The impact of p53 on aristolochic acid I-induced gene expression in vivo |
Organism |
Mus musculus |
Experiment type |
Expression profiling by array
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Summary |
Exposure to aristolochic acid (AA) is linked to kidney disease and urothelial cancer in humans. The major carcinogenic component of the AA plant extract is aristolochic acid I (AAI). The transcription factor p53 acts as a tumour suppressor and is frequently mutated in AA-induced tumours. Using a mouse model, we previously showed that Trp53 genotype impacts on AAI-induced nephrotoxicity in vivo (i.e. p53 protects from AAI-induced renal proximal tubular injury), but the underlying mechanism(s) involved remain to be further explored. In the present study, we investigated the impact of p53 on AAI-induced gene expression in vivo by treating Trp53(+/+), Trp53(+/-) and Trp53(-/-) mice with 3.5 mg/kg body weight (bw) AAI daily for 6 days. The Clariom™ S Assay microarray was used to elucidate gene expression profiles in mouse kidneys after AAI treatment in order to identify potential mechanisms by which AAI drives renal injury in Trp53(-/-) kidneys. Principle component analysis and hierarchical clustering in Qlucore Omics Explorer showed that gene expression in AAI-exposed Trp53(+/+), Trp53(+/-) and Trp53(-/-) kidneys is treatment-dependent. However, gene expression profiles did not segregate in a clear-cut manner according to Trp53 genotype, hence further investigations were performed by pathway analysis with MetaCore™. Several pathways, such as those related to epithelial-to-mesenchymal transition, transcription of hypoxia-inducible factor 1 targets, renal injury and secretion of xenobiotics were significantly altered to varying degrees for AAI-exposed kidneys. The top ten up-regulated genes included cyclin-dependent kinase inhibitor 1a (Cdkn1a), a mediator of cell cycle arrest; and neutrophil gelatinase-associated lipocalin (Ngal), which has been shown to play a role in nephritis by promoting inflammation and apoptosis. Members of the solute carrier (Slc) family (i.e. Slc22a2, Slc22a6, Slc22a7, Slc22a8) were amongst the top ten down-regulated genes. Pathway analysis also identified genes that are uniquely affected by AAI treatment in Trp53(+/+), Trp53(+/-) and Trp53(-/-) kidneys. Apoptotic pathways were modulated in Trp53(+/+) kidneys; whereas oncogenic and pro-survival pathways were significantly altered for Trp53(+/-) and Trp53(-/-) kidneys, respectively. Microarray gene expression analysis identified significant toxicogenomic responses to AAI that give novel insights into its mechanism of nephrotoxicity. Alterations of biological processes by AAI in Trp53(+/+), Trp53(+/-) and Trp53(-/-) kidneys could explain the mechanisms by which p53 protects from or p53 loss drives AAI-induced renal injury in vivo.
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Overall design |
Trp53(+/+), Trp53(+/-) and Trp53(-/-) mice were treated daily with 3.5 mg/kg body weight aristolochic acid I for 6 days (n = 5/group). Controls were treated with water only (n = 5/group). Total RNA was extracted from kidney tissues and the mouse Clariom™ S Assay was performed according to the manufacturer's instructions. Microarray data was analysed with TAC, QLUCORE and MetaCore softwares.
Microarray performed by Genomics Centre at King's College London.
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Contributor(s) |
Sborchia M, Keun HC, Phillips DH, Arlt VM |
Citation(s) |
31602497 |
Submission date |
Aug 23, 2019 |
Last update date |
Dec 06, 2019 |
Contact name |
Mateja Sborchia |
Organization name |
King's College London
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Department |
Analytical, Environmental and Forensic Sciences
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Lab |
Environmental Carcinogenesis
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Street address |
150 Stamford Street
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City |
London |
State/province |
Greater London |
ZIP/Postal code |
SE1 9NH |
Country |
United Kingdom |
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Platforms (1) |
GPL23038 |
[Clariom_S_Mouse] Affymetrix Clariom S Assay, Mouse (Includes Pico Assay) |
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Samples (30)
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Relations |
BioProject |
PRJNA561799 |
Supplementary file |
Size |
Download |
File type/resource |
GSE136276_RAW.tar |
32.0 Mb |
(http)(custom) |
TAR (of CEL) |
Processed data included within Sample table |
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