Abstract
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 tumour suppressor p53 is frequently mutated in AA-induced tumours. We previously showed that 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 by treating Trp53(+/+), Trp53(+/-), and Trp53(-/-) mice with 3.5 mg/kg body weight (bw) AAI daily for six days. The Clariom™ S Assay microarray was used to elucidate gene expression profiles in mouse kidneys after AAI treatment. Analyses in Qlucore Omics Explorer showed that gene expression in AAI-exposed 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 were significantly altered to varying degrees for AAI-exposed kidneys. Apoptotic pathways were modulated in Trp53(+/+) kidneys; whereas oncogenic and pro-survival pathways were significantly altered for Trp53(+/-) and Trp53(-/-) kidneys, respectively. Alterations of biological processes by AAI in mouse kidneys could explain the mechanisms by which p53 protects from or p53 loss drives AAI-induced renal injury in vivo.
Highlights
The p53 transcription factor regulates numerous cellular processes, including DNA repair, apoptosis, cell cycle arrest, and metabolism [1]
Which genes and pathways are modulated by aristolochic acid I (AAI) treatment in kidneys of Trp53(+/+), Trp53(+/-), and Trp53(-/-) mice?
Microarray analysis on AAI-exposed Trp53(+/+), Trp53(+/-), and Trp53(-/-) kidneys revealed treatment-dependent changes in gene expression and several biological pathways
Summary
The p53 transcription factor regulates numerous cellular processes, including DNA repair, apoptosis, cell cycle arrest, and metabolism [1]. More than 50% of human cancers are characterised by deregulations in TP53 [2,3]. Trp53(-/-) mice that develop cancers with complete penetrance [4,5]. Exposures to chemicals in the environment have been linked to characteristic TP53 mutational patterns in human tumours [6]. The environmental carcinogen aristolochic acid (AA) is present in Aristolochia plants which are used in medicinal herbal remedies worldwide [7,8]. The nitrophenanthrene carboxylic acid structure of AAI, which is the main component of the plant extract AA, is shown in Figure 1a [9,10]. Exposure to AA leads to particular DNA adducts that form as a result of AAI bioactivation by several enzymes, such as
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