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Series GSE136276 Query DataSets for GSE136276
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
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.
 
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.
 
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
Department Analytical, Environmental and Forensic Sciences
Lab Environmental Carcinogenesis
Street address 150 Stamford Street
City London
State/province Greater London
ZIP/Postal code SE1 9NH
Country United Kingdom
 
Platforms (1)
GPL23038 [Clariom_S_Mouse] Affymetrix Clariom S Assay, Mouse (Includes Pico Assay)
Samples (30)
GSM4043919 Kidney_WT_AAI_6 days_rep1
GSM4043920 Kidney_WT_AAI_6 days_rep2
GSM4043921 Kidney_WT_AAI_6 days_rep3
Relations
BioProject PRJNA561799

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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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