Ghai Vikas, Wu Xiaogang, Bheda-Malge Anjalei, Argyropoulos Christos P, Bernardo José F, Orchard Trevor, Galas David, Wang Kai
Institute for Systems Biology, Seattle, Washington, USA.
Department of Nephrology, University of New Mexico, Albuquerque, New Mexico, USA.
Kidney Int Rep. 2017 Dec 1;3(3):555-572. doi: 10.1016/j.ekir.2017.11.019. eCollection 2018 May.
Diabetic nephropathy (DN) is a form of progressive kidney disease that often leads to end-stage renal disease (ESRD). It is initiated by microvascular complications due to diabetes. Although microalbuminuria (MA) is the earliest clinical indication of DN among patients with type 1 diabetes (T1D), it lacks the sensitivity and specificity to detect the early onset of DN. Recently, microRNAs (miRNAs) have emerged as critical regulators in diabetes as well as various forms of kidney disease, including renal fibrosis, acute kidney injury, and progressive kidney disease. Additionally, circulating extracellular miRNAs, especially miRNAs packaged in extracellular vesicles (EVs), have garnered significant attention as potential noninvasive biomarkers for various diseases and health conditions.
As part of the University of Pittsburgh Epidemiology of Diabetes Complications (EDC) study, urine was collected from individuals with T1D with various grades of DN or MA (normal, overt, intermittent, and persistent) over a decade at prespecified intervals. We isolated EVs from urine and analyzed the small-RNA using NextGen sequencing.
We identified a set of miRNAs that are enriched in urinary EVs compared with EV-depleted samples, and identified a number of miRNAs showing concentration changes associated with DN occurrence, MA status, and other variables, such as hemoglobin A1c levels.
Many of the miRNAs associated with DN occurrence or MA status directly target pathways associated with renal fibrosis (including transforming growth factor-β and phosphatase and tensin homolog), which is one of the major contributors to the pathology of DN. These miRNAs are potential biomarkers for DN and MA.
糖尿病肾病（DN）是一种进行性肾脏疾病，常导致终末期肾病（ESRD）。它由糖尿病引起的微血管并发症引发。虽然微量白蛋白尿（MA）是1型糖尿病（T1D）患者中DN最早的临床指征，但它在检测DN早期发病方面缺乏敏感性和特异性。最近，微小RNA（miRNA）已成为糖尿病以及各种形式肾脏疾病（包括肾纤维化、急性肾损伤和进行性肾脏疾病）的关键调节因子。此外，循环细胞外miRNA，尤其是包裹在细胞外囊泡（EV）中的miRNA，作为各种疾病和健康状况的潜在非侵入性生物标志物已受到广泛关注。
作为匹兹堡大学糖尿病并发症流行病学（EDC）研究的一部分，在十年间按预定间隔从患有不同等级DN或MA（正常、显性、间歇性和持续性）的T1D个体中收集尿液。我们从尿液中分离出EV，并使用新一代测序分析小RNA。
我们鉴定出一组与去除EV的样本相比在尿EV中富集的miRNA，并鉴定出许多显示出与DN发生、MA状态以及其他变量（如糖化血红蛋白水平）相关的浓度变化的miRNA。
许多与DN发生或MA状态相关的miRNA直接靶向与肾纤维化相关的途径（包括转化生长因子-β和磷酸酶及张力蛋白同源物），肾纤维化是DN病理的主要促成因素之一。这些miRNA是DN和MA的潜在生物标志物。
