MicroRNA-34c-3p is an early predictive biomarker for doxorubicin-induced glomerular injury progression in male Sprague-Dawley rats
MicroRNA-34c-3p is an early predictive biomarker for doxorubicin-induced glomerular injury progression in male Sprague-Dawley rats
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DOI：
10.1039/c4tx00051j
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发表时间：
2014-01-01
影响因子：
2.1
通讯作者：
Harrill, Alison H.
中科院分区：
文献类型：
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作者：
Church, Rachel J.;McDuffie, J. Eric;Harrill, Alison H.
最近，有8种尿蛋白生物标志物在药物开发中有资格用于肾毒性预测；然而，肾小球毒性没有独特的生物标志物。蛋白尿是原发性肾小球损伤的标志性生物标志物，但缺乏特异性。与调节肾损伤的基因相关的MicroRNA物种可能被用作肾毒性的生物标志物。在这项研究中，除了组织病理学外，还评估了雄性Sprague-Dawley大鼠在每周静脉注射阿霉素（每剂量5mg kg(-1)）后尿液、血液和/或肾脏中microRNA和蛋白质表达的变化。第一次给药后，尿miRNA-34c-3p在第2天显著升高，并在第7天保持升高。尿骨桥蛋白仅在第2天显著升高。在没有组织病理学发现的情况下，第7天检测到明显的尿白蛋白。在第7天第二次给予阿霉素后，第14天检测到尿肾损伤分子1、胱抑素C、β 2微球蛋白、总蛋白和中性粒细胞明胶酶相关的脂钙蛋白浓度显著升高。这些改变与显著的进行性蛋白尿、尿miR-34c-3p、显著的显微镜下原发性肾小球损伤和继发性肾小管改变同时发生。尿miR-34c-3p升高可预测组织病理学损伤进展，优于传统的肾脏生物标志物，血清肌酐和血尿素氮，这些指标不随治疗而增加。与邻近非肾小球组织相比，受损肾小球中MiR-34c-3p也显著富集。总之，miR-34c-3p被认为是一种高度敏感的候选肾脏安全生物标志物，具有相对特异性，特别是在早期预测雄性Sprague-Dawley大鼠阿霉素诱导的肾小球损伤进展方面。
Recently, eight urinary protein biomarkers were qualified for renal toxicity prediction in drug development; however, there are no biomarkers unique to glomerular toxicity. Albuminuria is a hallmark biomarker for primary glomerular injury but lacks specificity. MicroRNA species associated with genes that regulate kidney injury could potentially be used as biomarkers of nephrotoxicity. In this study, microRNA and protein expression changes in urine, blood, and/or kidneys, in addition to histopathology were evaluated in male Sprague-Dawley rats following weekly intravenous injections of doxorubicin (5 mg kg(-1) per dose). Following the first administration, urinary miRNA-34c-3p was significantly increased on day 2 and remained elevated on day 7. Urinary osteopontin was significantly increased on day 2 only. Significant urinary albumin was detected on day 7, in the absence of histopathological findings. Following a second doxorubicin administration on day 7, significantly increased urinary kidney injury molecule 1, cystatin C, beta 2-microglobulin, total protein, and neutrophil gelatinase-associated lipocalin concentrations were detected on day 14. These alterations were concurrent to significant and progressive albuminuria, urinary miR-34c-3p, remarkable microscopic primary glomerular injury and secondary tubular alterations. Urinary miR-34c-3p elevations were predictive of histopathologic injury progression and outperformed the traditional renal biomarkers, serum creatinine and blood urea nitrogen, which did not increase with treatment. MiR-34c-3p was also significantly enriched in damaged glomeruli compared to adjacent non-glomerular tissue. Taken together, miR-34c-3p was identified as a highly sensitive candidate renal safety biomarker with relative specificity, particularly for early prediction of doxorubicin-induced glomerular injury progression in male Sprague-Dawley rats.