Department of Internal Medicine (Nephrology), Amsterdam University Medical Center, Amsterdam, the Netherlands.
Einthoven Laboratory for Vascular and Regenerative Medicine, Amsterdam University Medical Center, Amsterdam, the Netherlands.
Diabetes. 2019 Dec;68(12):2287-2300. doi: 10.2337/db18-1360. Epub 2019 Sep 10.
Previously, we identified plasma microRNA (miR) profiles that associate with markers of microvascular injury in patients with diabetic nephropathy (DN). However, miRs circulate in extracellular vesicles (EVs) or in association with HDL or the RNA-binding protein argonaute-2 (Ago-2). Given that the EV- and HDL-mediated miR transfer toward endothelial cells (ECs) regulates cellular quiescence and inflammation, we hypothesized that the distribution of miRs among carriers affects microvascular homeostasis in DN. Therefore, we determined the miR expression in EV, HDL, and Ago-2 fractions isolated from EDTA plasma of healthy control subjects, patients with diabetes mellitus (DM) with or without early DN (estimated glomerular filtration rate [eGFR] >30 mL/min/1.73 m), and patients with DN (eGFR <30 mL/min/1.73 m). Consistent with our hypothesis, we observed alterations in miR carrier distribution in plasma of patients with DM and DN compared with healthy control subjects. Both miR-21 and miR-126 increased in EVs of patients with DN, whereas miR-660 increased in the Ago-2 fraction and miR-132 decreased in the HDL fraction. Moreover, in vitro, differentially expressed miRs improved EC barrier formation (EV-miR-21) and rescued the angiogenic potential (HDL-miR-132) of ECs cultured in serum from patients with DM and DN. In conclusion, miR measurement in EVs, HDL, and Ago-2 may improve the biomarker sensitivity of these miRs for microvascular injury in DN, while carrier-specific miRs can improve endothelial barrier formation (EV-miR-21/126) or exert a proangiogenic response (HDL-miR-132).
先前，我们鉴定出与糖尿病肾病（DN）患者微血管损伤标志物相关的血浆 microRNA（miR）谱。然而，miR 循环存在于细胞外囊泡（EVs）中或与高密度脂蛋白（HDL）或 RNA 结合蛋白 Argonaute-2（Ago-2）结合。鉴于 EV 和 HDL 介导的 miR 向内皮细胞（EC）的转移调节细胞静止和炎症，我们假设 miR 在载体中的分布会影响 DN 中的微血管稳态。因此，我们测定了从健康对照者、患有糖尿病（DM）且有或无早期 DN（估计肾小球滤过率[eGFR]＞30 mL/min/1.73 m）的患者以及患有 DN（eGFR＜30 mL/min/1.73 m）的患者的 EDTA 血浆中分离的 EV、HDL 和 Ago-2 级分中的 miR 表达。与我们的假设一致，与健康对照者相比，我们观察到 DM 和 DN 患者的 miR 载体分布发生了改变。miR-21 和 miR-126 在 DN 患者的 EV 中增加，而 miR-660 在 Ago-2 级分中增加，miR-132 在 HDL 级分中减少。此外，在体外，差异表达的 miR 改善了 DM 和 DN 患者血清培养的 EC 屏障形成（EV-miR-21）和血管生成潜力（HDL-miR-132）。总之，EV、HDL 和 Ago-2 中的 miR 测量可能会提高这些 miR 对 DN 微血管损伤的生物标志物敏感性，而载体特异性 miR 可以改善内皮屏障形成（EV-miR-21/126）或发挥促血管生成作用（HDL-miR-132）。
