Endothelial extracellular vesicle miR-423-5p regulates microvascular homeostasis and renal function after ischemia-reperfusion injury.

IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Francis Migneault, Hyunyun Kim, Alice Doreille, Shanshan Lan, Alexis Gendron, Marie-Hélène Normand, Annie Karakeussian Rimbaud, Martin Dupont, Isabelle Bourdeau, Éric Bonneil, Julie Turgeon, Sylvie Dussault, Pierre Thibault, Mélanie Dieudé, Éric Boilard, Alain Rivard, Héloïse Cardinal, Marie-Josée Hébert
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Abstract

Microvascular rarefaction substantially contributes to renal dysfunction following ischemia-reperfusion injury (IRI). We characterized the microRNA signature of extracellular vesicles (EVs) released during endothelial apoptosis to identify biomarkers and regulators of microvascular rarefaction and renal dysfunction. Using in vitro models and RNA-Seq, we found miR-423-5p, let-7b-5p, and let-7c-5p enriched in small EVs from apoptotic endothelial cells. In mouse models of renal IRI and a cohort of 51 patients who have undergone renal transplant with delayed graft function, serum miR-423-5p correlated with circulating EVs, while let-7b-5p and let-7c-5p were also present in free form. Early acute kidney injury saw increased serum miR-423-5p levels linked to small EVs with endothelial markers. Over time, higher serum miR-423-5p levels were associated with large EVs and correlated with greater renal microvascular density and reduced fibrosis. Microvascular density and fibrosis predicted renal function 3 years after transplantation. We explored miR-423-5p's role in renal homeostasis, finding that its injection during renal IRI preserved microvascular density and inhibited fibrosis. Endothelial cells transfected with miR-423-5p showed enhanced resistance to apoptosis, increased migration, and angiogenesis. Localized miR-423-5p injection in hindlimb ischemia model accelerated revascularization. These findings position miR-423-5p as a predictor of renal microvascular rarefaction and fibrosis, highlighting potential strategies for preserving renal function.

内皮细胞外泡miR-423-5p调节缺血再灌注损伤后微血管稳态和肾功能。
微血管稀疏是缺血再灌注损伤(IRI)后肾功能不全的重要因素。我们对内皮细胞凋亡过程中释放的细胞外囊泡(EVs)的microRNA特征进行了表征,以确定微血管稀疏和肾功能障碍的生物标志物和调节因子。通过体外模型和RNA-Seq,我们发现miR-423-5p、let-7b-5p和let-7c-5p在凋亡内皮细胞的小ev中富集。在肾IRI小鼠模型和51例移植肾功能延迟的肾移植患者队列中,血清miR-423-5p与循环ev相关,而let-7b-5p和let-7c-5p也以游离形式存在。早期急性肾损伤的血清miR-423-5p水平升高与内皮标记的小ev相关。随着时间的推移,较高的血清miR-423-5p水平与较大的ev相关,并与较大的肾微血管密度和纤维化减少相关。微血管密度和纤维化预测移植后3年肾功能。我们探索了miR-423-5p在肾脏稳态中的作用,发现在肾脏IRI期间注射miR-423-5p可以保持微血管密度并抑制纤维化。转染miR-423-5p的内皮细胞对凋亡的抵抗增强,迁移增加,血管生成增加。局部注射miR-423-5p可促进后肢缺血模型血运重建。这些发现将miR-423-5p定位为肾脏微血管稀疏和纤维化的预测因子,强调了保留肾功能的潜在策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
JCI insight
JCI insight Medicine-General Medicine
CiteScore
13.70
自引率
1.20%
发文量
543
审稿时长
6 weeks
期刊介绍: JCI Insight is a Gold Open Access journal with a 2022 Impact Factor of 8.0. It publishes high-quality studies in various biomedical specialties, such as autoimmunity, gastroenterology, immunology, metabolism, nephrology, neuroscience, oncology, pulmonology, and vascular biology. The journal focuses on clinically relevant basic and translational research that contributes to the understanding of disease biology and treatment. JCI Insight is self-published by the American Society for Clinical Investigation (ASCI), a nonprofit honor organization of physician-scientists founded in 1908, and it helps fulfill the ASCI's mission to advance medical science through the publication of clinically relevant research reports.
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