Urine MicroRNA as Potential Biomarkers of Autosomal Dominant Polycystic Kidney Disease Progression: Description of miRNA Profiles at Baseline

BackgroundAutosomal dominant polycystic kidney disease (ADPKD) is clinically heterogenic. Biomarkers are needed to predict prognosis and guide management. We aimed to profile microRNA (miRNA) in ADPKD to gain molecular insight and evaluate biomarker potential.MethodsSmall-RNA libraries were generated from urine specimens of ADPKD patients (N = 20) and patients with chronic kidney disease of other etiologies (CKD, N = 20). In this report, we describe the miRNA profiles and baseline characteristics. For reference, we also examined the miRNA transcriptome in primary cultures of ADPKD cyst epithelia (N = 10), normal adult tubule (N = 8) and fetal tubule (N = 7) epithelia.ResultsIn primary cultures of ADPKD kidney cells, miRNA cistrons mir-143(2) (9.2-fold), let-7i(1) (2.3-fold) and mir-3619(1) (12.1-fold) were significantly elevated compared to normal tubule epithelia, whereas mir-1(4) members (19.7-fold), mir-133b(2) (21.1-fold) and mir-205(1) (3.0-fold) were downregulated (PConclusionsWe found that in ADPKD urine specimens, miRNA previously implicated as kidney tumor suppressors (miR-1 and miR-133), as well as miRNA of presumed inflammatory and fibroblast cell origin (miR-223/miR-199), are dysregulated when compared to other CKD patients. Concordant with findings in the primary tubule epithelial cell model, this suggests roles for dysregulated miRNA in ADPKD pathogenesis and potential use as biomarkers. We intend to assess prognostic potential of miRNA in a followup analysis.背景 常染色体显性遗传性多囊肾病（Autosomal dominant polycystic kidney disease, ADPKD）具有显著的临床异质性，目前亟需可用于预测预后、指导临床管理的生物标志物。本研究旨在对ADPKD患者体内的微RNA（microRNA, miRNA）进行表达谱分析，以解析其分子机制并评估其作为生物标志物的潜力。 方法 本研究从20例ADPKD患者与20例其他病因慢性肾脏病（chronic kidney disease, CKD）患者的尿液标本中构建小RNA文库。本报告将阐述miRNA表达谱及受试者的基线临床特征。此外，为提供参考对照，本研究同时检测了ADPKD囊肿上皮原代培养细胞（N=10）、正常成人肾小管上皮细胞（N=8）及胎儿肾小管上皮细胞（N=7）的miRNA转录组。 结果 与正常肾小管上皮细胞相比，ADPKD肾细胞原代培养体系中，miRNA基因簇mir-143(2)（表达上调9.2倍）、let-7i(1)（表达上调2.3倍）及mir-3619(1)（表达上调12.1倍）的水平显著升高；而mir-1(4)家族成员（表达下调19.7倍）、mir-133b(2)（表达下调21.1倍）及mir-205(1)（表达下调3.0倍）的水平显著降低（P < 0.05）。 结论 本研究发现，相较于其他CKD患者，ADPKD尿液标本中曾被证实为肾脏肿瘤抑制因子的miRNA（miR-1与miR-133），以及推测来源于炎症细胞与成纤维细胞的miRNA（miR-223/miR-199）均存在表达失调。这一结果与肾小管上皮原代细胞模型中的发现一致，提示表达失调的miRNA在ADPKD发病机制中发挥作用，且有望作为潜在生物标志物。本研究拟在后续分析中评估这些miRNA的预后预测价值。