Anglicheau Dany, Sharma Vijay K, Ding Ruchuang, Hummel Aurélie, Snopkowski Catherine, Dadhania Darshana, Seshan Surya V, Suthanthiran Manikkam
Division of Nephrology and Hypertension, Department of Medicine, New York Presbyterian-Weill Cornell Medical Center, New York, NY 10065, USA.
Proc Natl Acad Sci U S A. 2009 Mar 31;106(13):5330-5. doi: 10.1073/pnas.0813121106. Epub 2009 Mar 16.
Immune rejection of organ transplants is a life-threatening complication and is exemplified by alterations in the expression of protein-encoding genes. Because microRNAs (miRNAs) regulate the expression of genes implicated in adaptive immunity, we investigated whether acute rejection (AR) is associated with alterations in miRNA expression within allografts and whether expression profiles are diagnostic of AR and predict allograft function. Seven of 33 renal allograft biopsies (12 AR and 21 normal) were profiled using microfluidic cards containing 365 mature human miRNAs (training set), and a subset of differentially expressed miRNAs were quantified in the remaining 26 allograft biopsies (validation set). We found a strong association between intragraft expression of miRNAs and messenger RNAs (mRNAs), and that AR, and renal allograft function, could be predicted with a high level of precision using intragraft levels of miRNAs. Our investigation of miRNA expression in normal human peripheral blood mononuclear cells (PBMCs) showed that miRNAs (miR-142-5p, -155, and -223) overexpressed in AR biopsies are highly expressed in PBMCs, and that stimulation with the mitogen phytohaemagglutinin results in an increase in the abundance of miR-155 and a decrease in miR-223 and let-7c. Quantification of miRNAs in primary cultures of human renal epithelial cells (HRECs) showed that miR-30a-3p, -10b, and let-7c are highly expressed in HRECs, and that stimulation results in a decreased expression of miR-30a-3p. Our studies, in addition to suggesting a cellular basis for the altered intragraft expression of miRNAs, propose that miRNA expression patterns may serve as biomarkers of human renal allograft status.
器官移植的免疫排斥是一种危及生命的并发症，蛋白质编码基因表达的改变就是例证。由于微小RNA（miRNA）可调节与适应性免疫相关的基因表达，我们研究了急性排斥反应（AR）是否与同种异体移植物中miRNA表达的改变有关，以及表达谱是否可用于诊断AR并预测同种异体移植物功能。使用包含365种成熟人类miRNA的微流控芯片对33例肾移植活检组织中的7例（12例AR和21例正常）进行了分析（训练集），并在其余26例移植活检组织中对差异表达的miRNA子集进行了定量分析（验证集）。我们发现移植物内miRNA与信使RNA（mRNA）的表达之间存在密切关联，并且使用移植物内miRNA水平可以高精度预测AR和肾移植功能。我们对正常人类外周血单个核细胞（PBMC）中miRNA表达的研究表明，在AR活检组织中过表达的miRNA（miR-142-5p、-155和-223）在PBMC中也高度表达，并且用丝裂原植物血凝素刺激会导致miR-155丰度增加，miR-223和let-7c减少。对人肾上皮细胞（HREC）原代培养物中miRNA的定量分析表明，miR-30a-3p、-10b和let-7c在HREC中高度表达，并且刺激会导致miR-30a-3p表达降低。我们的研究除了为移植物内miRNA表达改变提供细胞基础外，还提出miRNA表达模式可能作为人类肾移植状态的生物标志物。
