Endothelial-Derived miR-17∼92 Promotes Angiogenesis to Protect against Renal Ischemia-Reperfusion Injury
Endothelial-Derived miR-17∼92 Promotes Angiogenesis to Protect against Renal Ischemia-Reperfusion Injury
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DOI：
10.1681/asn.2020050717
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发表时间：
2021-03-01
影响因子：
13.6
通讯作者：
Sims-Lucas, Sunder
中科院分区：
文献类型：
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作者：
Chiba, Takuto;Cerqueira, Debora M.;Sims-Lucas, Sunder
背景 肾微血管损伤是肾缺血再灌注损伤 (IRI) 介导的 AKI 的标志。与 92 miRNA 簇（编码 miR-17、-18a、-19a、-20a、-19b-1 和 -92a-1）相似的 miR-17 在多种情况下调节血管生成，但在 AKI 发病机制中肾内皮细胞中的明确作用尚未确定。方法利用与磁珠结合的抗体选择性富集小鼠肾内皮细胞。生成与 92 基因敲除相似的内皮特异性 miR-17（miR-17 与 92(endo-/-) 相似）小鼠并给予肾 IRI。使用血清化学和组织学监测小鼠 AKI 的发展，并使用磁共振成像 (MRI) 和激光多普勒成像监测肾血流量。在肾 IRI 期间用 miRNA 模拟物治疗小鼠，并评估治疗效果。结果肾IRI后肾内皮细胞中miR-17、-18a、-20a、-19b和与92相似的pri-miR-17受到动态调节。与 92(endo-/-) 类似的 miR-17 会加剧雄性和雌性小鼠的肾 IRI。具体来说，与92(endo-/-)相似的miR-17会促进肾小管损伤，减少肾血流量，促进微血管稀疏，增加肾脏氧化应激，并促进巨噬细胞浸润受损肾脏。强效抗血管生成因子血小板反应蛋白 1 (TSP1) 在肾 IRI 后肾内皮细胞中的 miR-17 中高表达，类似于 92(endo-/-)，并且是 miR-18a 和 miR-19a/b 的靶标。与 92 相似的 miR-17 在肾 IRI 后的血管生成反应中至关重要，用 miR-18a 和 miR-19b 模拟物治疗可以减轻这种反应。结论 这些数据表明，与 92 类似的内皮源性 miR-17 通过调节血管生成途径，刺激肾 IRI 期间受损肾脉管系统的修复反应。 意义说明 内皮细胞的调节在许多生物过程中很重要，包括发育、器官功能和疾病。肾脏脉管系统对缺氧损伤高度敏感，修复能力有限。血流减少导致的 AKI 很常见，目前尚无治疗方法。 MicroRNA 是抑制靶基因表达的小非编码 RNA。内皮源性 miR-17 与 92 类似，是一簇 microRNA，对于小鼠 AKI 期间的内皮功能和修复至关重要。此外，使用该簇的模拟物进行药物治疗可减轻 AKI，促进血管生成。这些 microRNA 是 AKI 后肾内皮损伤的第一个潜在治疗靶点，其模拟物可能广泛适用于涉及内皮损伤的疾病过程。
Background Damage to the renal microvasculature is a hallmark of renal ischemia-reperfusion injury (IRI)-mediated AKI. The miR-17 similar to 92 miRNA cluster (encoding miR-17, -18a, -19a, -20a, -19b-1, and -92a-1) regulates angiogenesis in multiple settings, but no definitive role in renal endothelium during AKI pathogenesis has been established. Methods Antibodies bound to magnetic beads were utilized to selectively enrich for renal endothelial cells from mice. Endothelial-specific miR-17 similar to 92 knockout (miR-17 similar to 92(endo-/-)) mice were generated and given renal IRI. Mice were monitored for the development of AKI using serum chemistries and histology and for renal blood flow using magnetic resonance imaging (MRI) and laser Doppler imaging. Mice were treated with miRNA mimics during renal IRI, and therapeutic efficacies were evaluated. Results miR-17, -18a, -20a, -19b, and pri-miR-17 similar to 92 are dynamically regulated in renal endothelial cells after renal IRI. miR-17 similar to 92(endo-/-) exacerbates renal IRI in male and female mice. Specifically, miR-17 similar to 92(endo-/-) promotes renal tubular injury, reduces renal blood flow, promotes microvascular rarefaction, increases renal oxidative stress, and promotes macrophage infiltration to injured kidneys. The potent antiangiogenic factor thrombospondin 1 (TSP1) is highly expressed in renal endothelium in miR-17 similar to 92(endo-/-) after renal IRI and is a target of miR-18a and miR-19a/b. miR-17 similar to 92 is critical in the angiogenic response after renal IRI, which treatment with miR-18a and miR-19b mimics can mitigate. Conclusions These data suggest that endothelial-derived miR-17 similar to 92 stimulates a reparative response in damaged renal vasculature during renal IRI by regulating angiogenic pathways.Significance Statement Regulation of endothelial cells is important in many biologic processes, including development, organ function, and disease. The kidney vasculature is highly sensitive to hypoxic injury and has a limited capacity for repair. AKI as a result of decreased blood flow is common, and there are no current therapies. MicroRNAs are small noncoding RNAs that inhibit expression of target genes. Endothelial-derived miR-17 similar to 92 is a cluster of microRNAs critical for endothelial function and repair during AKI in mice. Furthermore, pharmacologic treatment with mimics of the cluster mitigates AKI, promoting angiogenesis. These microRNAs are the first potential therapeutic target for kidney endothelial damage after AKI, and mimics may be broadly applicable to disease processes that involve endothelial injury.