MicroRNA expression profiles predictive of human renal allograft status
MicroRNA expression profiles predictive of human renal allograft status
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DOI：
10.1073/pnas.0813121106
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发表时间：
2009-03-31
影响因子：
11.1
通讯作者：
Suthanthiran, Manikkam
中科院分区：
文献类型：
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作者：
Anglicheau, Dany;Sharma, Vijay K.;Suthanthiran, Manikkam
器官移植的免疫排斥反应是一种威胁生命的并发症，蛋白质编码基因表达的变化就是例证。由于microRNAs(MiRNAs)调节与适应性免疫相关的基因的表达，我们研究了急性排斥(AR)是否与移植物内miRNA表达的变化有关，以及表达谱是否可用于AR的诊断和预测移植物的功能。33例移植肾活检中的7例(12例AR和21例正常)使用包含365个成熟人类miRNAs的微流控卡片(训练组)进行分析，在其余26例同种异体肾活检(验证组)中对差异表达的miRNAs进行了量化。我们发现在移植物内miRNAs和信使RNAs(MRNAs)的表达之间有很强的相关性，并且利用移植物内miRNAs的水平可以高精度地预测AR和同种异体肾功能。我们对正常人外周血单个核细胞(PBMCs)miRNA表达的研究表明，空气活检中过表达的miRNAs(miR-142-5p、-155和-223)在PBMC中高表达，有丝分裂原植物血凝素刺激导致miR-155丰度增加，miR-223和let-7c减少。对原代培养的人肾上皮细胞(HRECs)中miR-30a-3p、-10b和let-7c的定量检测表明，miR-30a-3p、-10b和let-7c在HRECs中高表达，而刺激导致miR-30a-3p表达降低。我们的研究，除了提示移植肾内miRNAs表达改变的细胞基础外，还提出miRNA表达模式可能作为人类移植肾状态的生物标志物。
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 AIR 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.