内皮细胞衍生的 促进血管生成以防止肾缺血再灌注损伤。
Endothelial-Derived Promotes Angiogenesis to Protect against Renal Ischemia-Reperfusion Injury.
机构信息
Division of Nephrology, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
Heart, Lung, Blood and Vascular Medicine Institute, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
出版信息
J Am Soc Nephrol. 2021 Mar;32(3):553-562. doi: 10.1681/ASN.2020050717. Epub 2021 Jan 29.
BACKGROUND
Damage to the renal microvasculature is a hallmark of renal ischemia-reperfusion injury (IRI)-mediated AKI. The miRNA cluster (encoding , , , , , and ) 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 knockout ( ) 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
, , , , and are dynamically regulated in renal endothelial cells after renal IRI. exacerbates renal IRI in male and female mice. Specifically, 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 after renal IRI and is a target of and . is critical in the angiogenic response after renal IRI, which treatment with and mimics can mitigate.
CONCLUSIONS
These data suggest that endothelial-derived stimulates a reparative response in damaged renal vasculature during renal IRI by regulating angiogenic pathways.
背景
肾脏微血管损伤是肾脏缺血再灌注损伤（IRI）介导的急性肾损伤（AKI）的标志。miRNA 簇（编码 miR-210-3p、miR-21、miR-146a、miR-155、miR-223 和 miR-486）在多种情况下调节血管生成，但在 AKI 发病机制中，其在肾脏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，从小鼠中选择性富集肾脏内皮细胞。生成内皮细胞特异性 miR-155 敲除（miR-155-/-）小鼠，并进行肾脏 IRI。通过血清化学和组织学监测 AKI 的发生，并通过磁共振成像（MRI）和激光多普勒成像监测肾脏血流。在肾脏 IRI 期间用 miRNA 模拟物治疗小鼠，并评估治疗效果。
结果
肾脏 IRI 后，肾脏内皮细胞中 miR-210-3p、miR-21、miR-146a、miR-155、miR-223 和 miR-486 呈动态调节。miR-155 在雄性和雌性小鼠的肾脏 IRI 中加重。具体而言，miR-155 促进肾小管损伤，减少肾脏血流，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伤的肾脏。在肾脏 IRI 后的肾脏内皮细胞中，强烈的抗血管生成因子血小板反应蛋白 1（TSP1）高度表达，并且是 miR-155 和 的靶标。在肾脏 IRI 后的血管生成反应中，miR-155 至关重要，用 miR-155 模拟物治疗可以减轻该反应。
结论
这些数据表明，内皮细胞衍生的 miR-155 通过调节血管生成途径刺激肾脏 IRI 中受损血管的修复反应。
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