Nassirpour Rounak, Homer Bruce L, Mathur Sachin, Li Yizheng, Li Zhonghan, Brown Tom, Carraher Deborah, Warneke James, Bailey Steven, Percival Karen, O'Neil Shawn P, Whiteley Laurence O
*Drug Safety, Pfizer Worldwide Research and Development;
Business Technology, Pfizer Research and Development, Andover, Massachusetts 01810; and.
Toxicol Sci. 2015 Nov;148(1):35-47. doi: 10.1093/toxsci/kfv167. Epub 2015 Aug 7.
MicroRNAs (miRNAs) are small, noncoding RNAs that regulate protein levels posttranscriptionally. miRNAs play important regulatory roles in many cellular processes and have been implicated in several diseases. Recent studies have reported significant levels of miRNAs in a variety of body fluids, raising the possibility that miRNAs could serve as useful biomarkers. Here, changes in miRNA expression patterns are described in 2 different rodent models of glomerular injury (acute puromycin aminonucleoside nephropathy and passive Heymann nephritis). By employing 2 different modes of glomerular insult, oxidative stress and immune-mediated toxicity, miRNA changes in both isolated glomeruli as well as urine specimens allow for identification of urinary miRNA biomarkers that are suggestive of drug-induced injury specifically to the glomerulus. Subsets of glomerular urinary miRNAs associated with these different modes of glomerular toxicity seem to be dependent on the mechanism of the induced injury, while 9 miRNAs that changed early in both glomerular and urine specimens were common to both studies. We further show that the miRNAs identified as mechanism-specific early glomerular injury biomarkers target key pathways and transcripts relevant to the type of insult, while the insult-independent changes might serve as ideal glomerular injury biomarkers.
微小RNA(miRNA)是一类小的非编码RNA,可在转录后调节蛋白质水平。miRNA在许多细胞过程中发挥重要的调节作用,并与多种疾病有关。最近的研究报道了多种体液中存在显著水平的miRNA,这增加了miRNA可作为有用生物标志物的可能性。在此,我们描述了两种不同的肾小球损伤啮齿动物模型(急性嘌呤霉素氨基核苷肾病和被动型Heymann肾炎)中miRNA表达模式的变化。通过采用两种不同的肾小球损伤模式,即氧化应激和免疫介导的毒性作用,分离的肾小球以及尿液标本中的miRNA变化使得能够鉴定出提示药物诱导的特异性肾小球损伤的尿液miRNA生物标志物。与这些不同的肾小球毒性模式相关的肾小球尿液miRNA亚群似乎取决于诱导损伤的机制,而在两项研究中,肾小球和尿液标本中早期均发生变化的9种miRNA是共有的。我们进一步表明,被鉴定为机制特异性早期肾小球损伤生物标志物的miRNA靶向与损伤类型相关的关键途径和转录本,而与损伤无关的变化可能是理想的肾小球损伤生物标志物。