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Understanding the aristolochic acid toxicities in rat kidneys with regulatory networks.

ABSTRACT: The natural products containing aristolochic acid (AA) have been widely used for acne, gastritis and so on. Recently, it is becoming accepted that AA may be responsible for acute and chronic renal failures as the side effects of Chinese herbs. However, it is unclear what happens in the cells after the AA treatment. In this study, the authors built a gene regulatory network as well as a microRNA-gene regulatory network to investigate the molecular dynamics induced by AA from a systematic perspective. With the regulatory networks, they detected some important pathways and biological processes that were affected by AA treatment, which can help explain the nephrotoxicity and carcinogenicity of AA. They found some important regulators and genes responding to AA treatment, and these genes have been reported to be related to the kidney functions, indicating their important roles in the toxicity of AA.

SUBMITTER: Wang YY

PROVIDER: S-EPMC8687369 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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Understanding the aristolochic acid toxicities in rat kidneys with regulatory networks.

Wang Yin-Ying YY Li Zhiguang Z Chen Tao T Zhao Xing-Ming XM

IET systems biology 20150801 4

The natural products containing aristolochic acid (AA) have been widely used for acne, gastritis and so on. Recently, it is becoming accepted that AA may be responsible for acute and chronic renal failures as the side effects of Chinese herbs. However, it is unclear what happens in the cells after the AA treatment. In this study, the authors built a gene regulatory network as well as a microRNA-gene regulatory network to investigate the molecular dynamics induced by AA from a systematic perspect ...[more]

PMID: 26243830

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Project description:BackgroundAristolochic Acid (AA), a natural component of Aristolochia plants that is found in a variety of herbal remedies and health supplements, is classified as a Group 1 carcinogen by the International Agency for Research on Cancer. Given that microRNAs (miRNAs) are involved in cancer initiation and progression and their role remains unknown in AA-induced carcinogenesis, we examined genome-wide AA-induced dysregulation of miRNAs as well as the regulation of miRNAs on their target gene expression in rat kidney.ResultsWe treated rats with 10 mg/kg AA and vehicle control for 12 weeks and eight kidney samples (4 for the treatment and 4 for the control) were used for examining miRNA and mRNA expression by deep sequencing, and protein expression by proteomics. AA treatment resulted in significant differential expression of miRNAs, mRNAs and proteins as measured by both principal component analysis (PCA) and hierarchical clustering analysis (HCA). Specially, 63 miRNAs (adjusted p value < 0.05 and fold change > 1.5), 6,794 mRNAs (adjusted p value < 0.05 and fold change > 2.0), and 800 proteins (fold change > 2.0) were significantly altered by AA treatment. The expression of 6 selected miRNAs was validated by quantitative real-time PCR analysis. Ingenuity Pathways Analysis (IPA) showed that cancer is the top network and disease associated with those dysregulated miRNAs. To further investigate the influence of miRNAs on kidney mRNA and protein expression, we combined proteomic and transcriptomic data in conjunction with miRNA target selection as confirmed and reported in miRTarBase. In addition to translational repression and transcriptional destabilization, we also found that miRNAs and their target genes were expressed in the same direction at levels of transcription (169) or translation (227). Furthermore, we identified that up-regulation of 13 oncogenic miRNAs was associated with translational activation of 45 out of 54 cancer-related targets.ConclusionsOur findings suggest that dysregulated miRNA expression plays an important role in AA-induced carcinogenesis in rat kidney, and that the integrated approach of multiple profiling provides a new insight into a post-transcriptional regulation of miRNAs on their target repression and activation in a genome-wide scale.

Project description:RNA-Seq has been increasingly used for the quantification and characterization of transcriptomes. The ongoing development of the technology promises the more accurate measurement of gene expression. However, its benefits over widely accepted microarray technologies have not been adequately assessed, especially in toxicogenomics studies. The goal of this study is to enhance the scientific community's understanding of the advantages and challenges of RNA-Seq in the quantification of gene expression by comparing analysis results from RNA-Seq and microarray data on a toxicogenomics study. A typical toxicogenomics study design was used to compare the performance of an RNA-Seq approach (Illumina Genome Analyzer II) to a microarray-based approach (Affymetrix Rat Genome 230 2.0 arrays) for detecting differentially expressed genes (DEGs) in the kidneys of rats treated with aristolochic acid (AA), a carcinogenic and nephrotoxic chemical most notably used for weight loss. We studied the comparability of the RNA-Seq and microarray data in terms of absolute gene expression, gene expression patterns, differentially expressed genes, and biological interpretation. We found that RNA-Seq was more sensitive in detecting genes with low expression levels, while similar gene expression patterns were observed for both platforms. Moreover, although the overlap of the DEGs was only 40-50%, the biological interpretation was largely consistent between the RNA-Seq and microarray data. RNA-Seq maintained a consistent biological interpretation with time-tested microarray platforms while generating more sensitive results. However, there is clearly a need for future investigations to better understand the advantages and limitations of RNA-Seq in toxicogenomics studies and environmental health research. Eight rats were randomly divided into two groups: four rats were administered with aristolochic acid (AA), and four rats were treated with the control vehicle. RNA samples were extracted from the kidney tissue of each rat and were independently assayed with both the NGS (Illumina Genome Analyzer II) and the microarray (Affymetrix Rat Genome 230 2.0) platforms. The RNA-Seq and microarray data were compared in terms of absolute gene expression, gene expression patterns, differentially expressed genes, and biological interpretation.

Dataset Information

Understanding the aristolochic acid toxicities in rat kidneys with regulatory networks.

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Understanding the aristolochic acid toxicities in rat kidneys with regulatory networks.

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