Urinary miRNA Biomarkers of Drug-Induced Kidney Injury and Their Site Specificity Within the Nephron.
Urinary miRNA Biomarkers of Drug-Induced Kidney Injury and Their Site Specificity Within the Nephron.
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DOI：
10.1093/toxsci/kfaa181
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发表时间：
2021-02-26
期刊：
影响因子：
--
通讯作者：
Gautier JC
中科院分区：
文献类型：
--
作者：
Chorley BN;Ellinger-Ziegelbauer H;Tackett M;Simutis FJ;Harrill AH;McDuffie J;Atabakhsh E;Nassirpour R;Whiteley LO;Léonard JF;Carswell GK;Harpur E;Chen CL;Gautier JC
药物性肾损伤（DIKI）是药物开发和临床实践中的一个主要问题。对肾小球损伤和Henle袢和集合管（CD）中更远端肾损伤的生物标志物的需求尚未得到满足。进行了一项跨实验室项目，以鉴定和表征反映组织或病理学特异性DIKI的尿microRNA（miRNA）模式。总体目标是提出DIKI的miRNA生物标志物候选物，可以补充尿液中蛋白质肾脏生物标志物提供的信息。用肾毒物处理大鼠，引起不同肾单位节段的损伤：肾小球、近端小管、Henle袢和CD的粗升支（TAL）。荟萃分析将miR-192- 5 p确定为潜在的近端小管特异性尿miRNA候选者。这一结果得到了激光捕获显微切割肾单位片段中获得的数据的支持，显示miR-192- 5 p表达在近端小管中富集。根据其在肾脏中的表达定位，在用TAL与近端小管毒物处理的大鼠的尿液中，包括miR-221- 3 p和-222-3p的区别性miRNA增加。在用TAL毒物处理后，尿miR-210- 3 p增加高达40倍，并且在含有TAL和/或CD的激光捕获显微切割样品中相对于近端小管也富集。miR-23 a-3 p在肾小球中富集，并且在用阿霉素（肾小球毒物）处理的大鼠的尿液中增加，但在影响其他肾单位节段的毒物中则没有。总之，这些结果表明，来源于特定肾单位区域的尿miRNA组可能有助于区分肾脏中毒物诱导的病变的病理学，从而有助于DIKI生物标志物开发用于工业、临床和监管用途的需求。
Drug-induced kidney injury (DIKI) is a major concern in both drug development and clinical practice. There is an unmet need for biomarkers of glomerular damage and more distal renal injury in the loop of Henle and the collecting duct (CD). A cross-laboratory program to identify and characterize urinary microRNA (miRNA) patterns reflecting tissue- or pathology-specific DIKI was conducted. The overall goal was to propose miRNA biomarker candidates for DIKI that could supplement information provided by protein kidney biomarkers in urine. Rats were treated with nephrotoxicants causing injury to distinct nephron segments: the glomerulus, proximal tubule, thick ascending limb (TAL) of the loop of Henle and CD. Meta-analysis identified miR-192-5p as a potential proximal tubule-specific urinary miRNA candidate. This result was supported by data obtained in laser capture microdissection nephron segments showing that miR-192-5p expression was enriched in the proximal tubule. Discriminative miRNAs including miR-221-3p and -222-3p were increased in urine from rats treated with TAL versus proximal tubule toxicants in accordance with their expression localization in the kidney. Urinary miR-210-3p increased up to 40-fold upon treatment with TAL toxicants and was also enriched in laser capture microdissection samples containing TAL and/or CD versus proximal tubule. miR-23a-3p was enriched in the glomerulus and was increased in urine from rats treated with doxorubicin, a glomerular toxicant, but not with toxicants affecting other nephron segments. Taken together these results suggest that urinary miRNA panels sourced from specific nephron regions may be useful to discriminate the pathology of toxicant-induced lesions in the kidney, thereby contributing to DIKI biomarker development needs for industry, clinical, and regulatory use.
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