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首页> 外文期刊>Journal of applied toxicology >Comprehensive expression analysis of mRNA and microRNA for the investigation of compensatory mechanisms in the rat kidney after unilateral nephrectomy
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Comprehensive expression analysis of mRNA and microRNA for the investigation of compensatory mechanisms in the rat kidney after unilateral nephrectomy

机译:mRNA和microRNA综合表达分析,用于单侧肾切除术大鼠肾脏补偿机制调查

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Compensation is a physiological response that occurs during chemical exposure to maintain homeostasis. Because compensatory responses are not usually considered adverse effects, it is important to understand compensatory mechanisms for chemical risk assessment. Although the kidney is a major target organ for toxicity, there is controversy over whether hyperplasia or hypertrophy contributes to the compensatory mechanism, and there is limited information to apply for chemical risk assessment. In the present study, compensatory mechanisms of the kidney were investigated in a unilateral nephrectomy (UNx) model using adult male and female F344 rats. In residual kidneys of male and female rats after UNx, 5-bromo-2 '-deoxyuridine-labeling indices and mRNA expression of cell cycle-related genes were increased, although there were no fluctuations in mRNA expression of transforming growth factor-beta 1, which contributes to hypertrophy in renal tubules. Pathway analysis using mRNA expression data from a complementary DNA (cDNA) microarray revealed that canonical pathways related to cell proliferation were mainly activated and that forkhead box M1 (FOXM1) was an upstream regulator of compensatory cell proliferation in residual kidneys of male and female rats. cDNA microarray for microRNAs (miRNAs) demonstrated that nine miRNAs were downregulated in residual kidneys, and mRNA/miRNA integrated analysis indicated that miRNAs were associated with the expression of factors downstream of FOXM1. Overall, these results suggested that FOXM1-mediated hyperplasia rather than hypertrophy contributed to compensatory mechanisms in the kidney and that miRNAs regulated downstream FOXM1 signaling. These results will be beneficial for evaluating nephrotoxicity in chemical risk assessment and for developing new biomarkers to predict nephrotoxicity.
机译:补偿是一种生理反应,发生在化学暴露期间,以维持体内平衡。由于补偿反应通常不被视为有害影响,因此了解补偿机制对于化学品风险评估非常重要。尽管肾脏是毒性的主要靶器官,但对于增生或肥大是否有助于代偿机制仍存在争议,而且申请化学风险评估的信息也有限。在本研究中,我们使用成年雄性和雌性F344大鼠在单侧肾切除(UNx)模型中研究了肾脏的代偿机制。在UNx后雄性和雌性大鼠的残余肾脏中,5-溴-2'-脱氧尿苷标记指数和细胞周期相关基因的mRNA表达增加,尽管转化生长因子β1的mRNA表达没有波动,这有助于肾小管肥大。利用互补DNA(cDNA)微阵列的mRNA表达数据进行的通路分析显示,与细胞增殖相关的典型通路主要被激活,叉头盒M1(FOXM1)是雄性和雌性大鼠残余肾脏代偿性细胞增殖的上游调节器。microRNA(miRNA)的cDNA微阵列显示,9个miRNA在残余肾脏中下调,mRNA/miRNA整合分析表明,miRNA与FOXM1下游因子的表达相关。总的来说,这些结果表明FOXM1介导的增生而不是肥大有助于肾脏的代偿机制,并且miRNA调节下游的FOXM1信号。这些结果将有助于在化学风险评估中评估肾毒性,并开发新的生物标记物来预测肾毒性。

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