Microvesicles derived from endothelial progenitor cells protect the kidney from ischemia-reperfusion injury by microRNA-dependent reprogramming of resident renal cells
Microvesicles derived from endothelial progenitor cells protect the kidney from ischemia-reperfusion injury by microRNA-dependent reprogramming of resident renal cells
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DOI：
10.1038/ki.2012.105
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发表时间：
2012-08-01
影响因子：
19.6
通讯作者：
Camussi, Giovanni
中科院分区：
文献类型：
--
作者：
Cantaluppi, Vincenzo;Gatti, Stefano;Camussi, Giovanni
已知内皮祖细胞通过旁分泌机制逆转急性肾损伤。我们先前发现，从这些祖细胞释放的微泡通过水平mRNA转移激活内皮细胞中的血管生成程序。在这里，我们测试了这些微泡是否能预防缺血再灌注损伤大鼠模型的急性肾损伤。微囊泡的RNA内容物富含调节增殖、血管生成和凋亡的微小RNA（miRNAs）。缺血-再灌注后静脉注射后，微泡定位于肾小管周围毛细血管和肾小管细胞内。这通过增强肾小管细胞增殖、减少细胞凋亡和白细胞浸润而赋予急性肾损伤的功能和形态保护。微泡还通过抑制毛细血管稀疏、肾小球硬化和肾小管间质纤维化来防止慢性肾损伤的进展。用RNase处理后，微泡的肾保护作用丧失，通过在祖细胞中敲低Dicer而非特异性地消耗微泡的miRNA，或通过用特异性miR-miR-126和miR-296转染而消耗促血管生成的miR-126和miR-296。因此，来源于内皮祖细胞的微泡通过递送其RNA内容物来保护肾脏免受缺血性急性损伤，其miRNA货物有助于将缺氧的常驻肾细胞重编程为再生程序。Kidney International（2012）82，412-427; doi：10.1038/ki.2012.105; 2012年4月11日在线发表
Endothelial progenitor cells are known to reverse acute kidney injury by paracrine mechanisms. We previously found that microvesicles released from these progenitor cells activate an angiogenic program in endothelial cells by horizontal mRNA transfer. Here, we tested whether these microvesicles prevent acute kidney injury in a rat model of ischemia-reperfusion injury. The RNA content of microvesicles was enriched in microRNAs (miRNAs) that modulate proliferation, angiogenesis, and apoptosis. After intravenous injection following ischemia-reperfusion, the microvesicles were localized within peritubular capillaries and tubular cells. This conferred functional and morphologic protection from acute kidney injury by enhanced tubular cell proliferation, reduced apoptosis, and leukocyte infiltration. Microvesicles also protected against progression of chronic kidney damage by inhibiting capillary rarefaction, glomerulosclerosis, and tubulointerstitial fibrosis. The renoprotective effect of microvesicles was lost after treatment with RNase, nonspecific miRNA depletion of microvesicles by Dicer knock-down in the progenitor cells, or depletion of pro-angiogenic miR-126 and miR-296 by transfection with specific miR-antagomirs. Thus, microvesicles derived from endothelial progenitor cells protect the kidney from ischemic acute injury by delivering their RNA content, the miRNA cargo of which contributes to reprogramming hypoxic resident renal cells to a regenerative program.Kidney International (2012) 82, 412-427; doi:10.1038/ki.2012.105; published online 11 April 2012