From the Cardiometabolic and Renal Risk Research Group, INCLIVA Biomedical Research Institute, Valencia, Spain (J.P.-H., A.O., O.M.-A., D.P.-G., D.O., E.S., F.M., J.R., R.C.).
Departamento de Anatomía Patológica, Facultad de Medicina, Universidad de La Frontera, Temuco, Chile (A.L.R.-C.).
Hypertension. 2021 Mar 3;77(3):960-971. doi: 10.1161/HYPERTENSIONAHA.120.16598. Epub 2021 Jan 25.
Urinary albumin excretion (UAE) is a marker of cardiovascular risk and renal damage in hypertension. MicroRNAs (miRNAs) packaged into exosomes function as paracrine effectors in cell communication and the kidney is not exempt. This study aimed to state an exosomal miRNA profile/signature associated to hypertension with increased UAE and the impact of profibrotic TGF-β1 (transforming growth factor β1) on exosomes miRNA release. Therefore, exosomes samples from patients with hypertension with/without UAE were isolated and characterized. Three individual and unique small RNA libraries from each subject were prepared (total plasma, urinary, and plasma-derived exosomes) for next-generation sequencing profiling. Differentially expressed miRNAs were over-represented in Kyoto Encyclopedia of Genes and Genomes pathways, and selected miRNAs were validated by real-time quantitative polymerase chain reaction in a confirmation cohort. Thus, a signature of 29 dysregulated circulating miRNAs was identified in UAE hypertensive subjects, regulating 21 pathways. Moreover, changes in the levels of 4 exosomes-miRNAs were validated in a confirmation cohort and found associated with albuminuria. In particular miR-26a, major regulator of TGF-β signaling, was found downregulated in both type of exosomes when compared with healthy controls and to hypertension normoalbuminurics (<0.01). Similarly, decreased miR-26a levels were found in podocyte-derived exosomes after TGF-β stress. Our results revealed an exosomes miRNA signature associated to albuminuria in hypertension. In particular, exosomes miR-26a seemed to play a key role in the regulation of TGF-β, a relevant effector in podocyte damage. These findings support the use of exosomes miRNAs as biomarkers of cardiovascular risk progression and therapeutic tools in early kidney damage.
尿白蛋白排泄率（UAE）是高血压患者心血管风险和肾脏损害的标志物。包裹在细胞外囊泡中的 microRNAs（miRNAs）作为旁分泌效应物在细胞通讯中发挥作用，肾脏也不例外。本研究旨在描述与 UAE 增加相关的高血压患者的外泌体 miRNA 图谱/特征，以及促纤维化 TGF-β1（转化生长因子 β1）对 exosomes miRNA 释放的影响。因此，分离并鉴定了高血压伴/不伴 UAE 患者的外泌体样本。从每位患者的总血浆、尿液和血浆衍生的外泌体中分别制备了三个个体和独特的小 RNA 文库，进行下一代测序分析。差异表达的 miRNAs 在京都基因与基因组百科全书中的途径中被过度表达，选择的 miRNAs 通过实时定量聚合酶链反应在验证队列中进行验证。因此，在 UAE 高血压患者中鉴定出 29 个失调的循环 miRNAs 特征，调节 21 条途径。此外，在验证队列中验证了 4 个外泌体 miRNA 的水平变化，发现与白蛋白尿有关。特别是 miR-26a，TGF-β 信号的主要调节因子，在与健康对照组和高血压正常白蛋白尿组相比时，在两种类型的外泌体中均下调（<0.01）。类似地，在 TGF-β 应激后，足细胞衍生的外泌体中也发现 miR-26a 水平降低。我们的结果揭示了与高血压白蛋白尿相关的外泌体 miRNA 特征。特别是，外泌体 miR-26a 似乎在 TGF-β 的调节中发挥关键作用，TGF-β 是足细胞损伤的一个重要效应物。这些发现支持将外泌体 miRNAs 用作心血管风险进展的生物标志物和早期肾脏损伤的治疗工具。
