Division of Nephrology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
Graduate Institute of Pharmacology, National Taiwan University College of Medicine, Taipei, Taiwan.
Int J Cardiol. 2019 Feb 15;277:212-219. doi: 10.1016/j.ijcard.2018.08.013. Epub 2018 Aug 7.
Cardiovascular (CV) diseases are major causes of mortality in uremic patients. Conventional risk factors fail to identify uremic patients with increased propensity for adverse CV outcomes. We aimed to test the hypothesis that circulating long noncoding RNAs (lncRNAs) could be a prognostic marker to predict adverse CV outcomes in uremic patients.
Plasma lncRNAs were profiled in patients with end-stage renal disease (ESRD, n = 28) or chronic kidney disease (CKD, n = 8) and in healthy (n = 12) subjects by RNA sequencing. A total of 179 lncRNAs were significantly dysregulated with ESRD; the expression signature of plasma lncRNAs distinguished ESRD from both CKD and control samples. Analysis on a microarray dataset obtained from renal biopsy samples of patients with advanced kidney disease (GSE66494) revealed that a significant proportion of plasma lncRNAs (30.7%) and mRNAs (49.5%) dysregulated with uremia were similarly dysregulated in diseased kidneys, suggesting that plasma RNA profiles mirror the transcriptomal changes in diseased kidney tissues. Further analyses identified eight plasma lncRNAs as potential predictors of adverse CV outcomes in uremic patients. Validation study in an independent cohort of ESRD patients (n = 111) confirmed that elevated plasma lncRNA DKFZP434I0714 is a significant independent predictor of adverse CV outcomes in uremic patients. Additional experiments demonstrated the functional involvement of DKFZP434I0714 in the pathogenesis of endothelial dysfunction.
In summary, plasma lncRNA expression signature reflects the disease states of uremia. Elevated plasma levels of lncRNA DKFZP434I0714 in uremic patients portend a worse CV outcome and warrant closer monitoring and more aggressive management.
心血管疾病是尿毒症患者死亡的主要原因。传统的危险因素无法识别易发生不良心血管结局的尿毒症患者。我们旨在检验循环长链非编码 RNA（lncRNA）是否可以作为预测尿毒症患者不良心血管结局的预后标志物的假说。
通过 RNA 测序对终末期肾病（ESRD，n=28）或慢性肾脏病（CKD，n=8）患者和健康对照（n=12）的血浆 lncRNA 进行了分析。共有 179 个 lncRNA 与 ESRD 显著失调；血浆 lncRNA 的表达谱可将 ESRD 与 CKD 和对照样本区分开来。对来自进展性肾病患者肾活检样本的微阵列数据集（GSE66494）进行分析显示，与尿毒症相关的大量血浆 lncRNA（30.7%）和 mRNA（49.5%）失调，在病变肾脏中也存在相似的失调，这表明血浆 RNA 谱反映了病变肾脏组织中的转录组变化。进一步的分析确定了 8 个血浆 lncRNA 作为尿毒症患者不良心血管结局的潜在预测因子。在另一个 ESRD 患者独立队列（n=111）的验证研究中证实，升高的血浆 lncRNA DKFZP434I0714 是尿毒症患者不良心血管结局的一个显著独立预测因子。额外的实验表明，lncRNA DKFZP434I0714 在血管内皮功能障碍的发病机制中具有功能作用。
总之，血浆 lncRNA 表达谱反映了尿毒症的疾病状态。尿毒症患者血浆中 lncRNA DKFZP434I0714 水平升高预示着心血管结局较差，需要更密切的监测和更积极的治疗。
