Cardiometabolic and Renal Risk Research Group, INCLIVA Health Research Institute, Avd. Menenzdez Pelayo, acceso 4, 46010, Valencia, Spain.
NSERM, U1016, I, Cochin Institute, 75014, Paris, France.
J Nephrol. 2021 Aug;34(4):1157-1167. doi: 10.1007/s40620-020-00832-y. Epub 2020 Aug 16.
Urinary exosomes, especially microRNAs (miRNAs) packaged within, are ideal sources of renal damage markers. We investigated the association between exosomal miR-146a, (anti-inflammatory regulator) and disease activity, proteinuria and systemic lupus erythematosus (SLE) flares over a 36-month follow-up period.
We isolated urinary exosomes from 41 SLE patients, 27 with lupus nephritis (LN) and 20 healthy controls, and exosomal miR-146a, quantified by the real-time quantitative polymerase chain reaction (RT-qPCR), was correlated with histological features in 13 renal biopsies. We also analysed the association between the exosomal miR-146a and TRAF6 axis.
Exosomal miR-146a showed an inverse association with circulating C3 and C4 complement components, proteinuria, and with histological features such as chronicity index. This marker was able to identify LN with an AUC of 0.82 (p = 0.001). Basal exosomal miR-146a was associated with disease activity and proteinuria changes and was an independent marker of 36-month follow-up flares (OR 7.08, p = 0.02). Pathway analysis identified IRAK1 and TRAF6 as miR-146a target genes. Finally, in vitro experiments suggested that miR-146a exerts a protective effect through negative regulation of inflammation by suppressing IRAK1 and TRAF6.
Urinary exosomal miR-146a levels are correlated with lupus activity, proteinuria and histological features, discriminating patients with LN and being a good baseline marker of SLE flares. We have identified a relevant biological miR-146a-TRAF6 axis association in LN renal fibrosis progression.
尿液外泌体，尤其是其中包裹的 microRNAs（miRNAs），是肾脏损伤标志物的理想来源。我们研究了在 36 个月的随访期间，外泌体 miR-146a（抗炎调节剂）与疾病活动度、蛋白尿和系统性红斑狼疮（SLE） flares 之间的关联。
我们从 41 名 SLE 患者、27 名狼疮肾炎（LN）患者和 20 名健康对照者中分离尿液外泌体，通过实时定量聚合酶链反应（RT-qPCR）定量外泌体 miR-146a，并在 13 例肾活检中分析其与组织学特征的相关性。我们还分析了外泌体 miR-146a 与 TRAF6 轴之间的关系。
外泌体 miR-146a 与循环 C3 和 C4 补体成分、蛋白尿呈负相关，与慢性指数等组织学特征也呈负相关。该标志物能够以 0.82 的 AUC 识别 LN（p=0.001）。基础外泌体 miR-146a 与疾病活动度和蛋白尿变化相关，是 36 个月随访 flares 的独立标志物（OR 7.08，p=0.02）。通路分析确定 IRAK1 和 TRAF6 为 miR-146a 的靶基因。最后，体外实验表明，miR-146a 通过抑制 IRAK1 和 TRAF6 对炎症的负调控发挥保护作用。
尿液外泌体 miR-146a 水平与狼疮活动度、蛋白尿和组织学特征相关，可区分 LN 患者，是 SLE flares 的良好基线标志物。我们已经确定了 LN 肾纤维化进展中相关的生物学 miR-146a-TRAF6 轴关联。
