Podocyte-Released Migrasomes in Urine Serve as an Indicator for Early Podocyte Injury
Podocyte-Released Migrasomes in Urine Serve as an Indicator for Early Podocyte Injury
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尿液中足细胞释放的迁移体可作为早期足细胞损伤的指标
DOI：
10.1159/000511504
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发表时间：
2020-11-01
期刊：
影响因子：
3.7
通讯作者：
Zen, Ke
中科院分区：
文献类型：
--
作者：
Liu, Ying;Li, Shan;Zen, Ke
背景：尿微泡水平在各种肾脏损伤中增加，具有诊断肾脏疾病的潜力。然而，尿微泡作为肾脏疾病指标的重要性受到难以确定其细胞来源的影响。目的：本研究的目的是证明足细胞可以释放migrasomes，这是一类独特的微泡，大小在400和2,000 nm之间，尿中migrasomes的水平可以作为早期足细胞损伤的新的非侵入性生物标志物。方法：在这项研究中，免疫荧光标记，电子显微镜，nanosite，和顺序离心纯化和分析migrasomes。结果：足细胞释放的移行体与外泌体有不同的含量和释放机制。与足细胞相比，肾小管细胞分泌的移行体明显较少。此外，在LPS、嘌呤霉素氨基核苷（PAN）或高浓度葡萄糖（HG）诱导的足细胞损伤过程中，人或小鼠足细胞的移行体分泌强烈增强。然而，LPS、PAN或HG诱导的足细胞移行体释放被Rac-1抑制剂阻断。值得注意的是，PAN肾病小鼠尿液中的足细胞移行体水平高于对照小鼠。事实上，在PAN肾病期间检测到尿移行体数量增加早于蛋白尿升高，表明尿移行体是比蛋白尿更敏感的足细胞损伤指标。蛋白尿<5.5g/d的糖尿病肾病患者尿中移行小体数量也增加。结论：我们的研究结果表明，足细胞在迁移过程中释放“损伤相关”的迁移体，并提供尿足细胞迁移体作为早期足细胞损伤的潜在诊断标志物。
Background: Levels of urinary microvesicles, which are increased during various kidney injuries, have diagnostic potential for renal diseases. However, the significance of urinary microvesicles as a renal disease indicator is dampened by the difficulty to ascertain their cell source. Objectives: The aim of this study was to demonstrate that podocytes can release migrasomes, a unique class of microvesicle with size ranging between 400 and 2,000 nm, and the urine level of migrasomes may serve as novel non-invasive biomarker for early podocyte injury. Method: In this study, immunofluorescence labeling, electronic microscopy, nanosite, and sequential centrifugation were used to purify and analyze migrasomes. Results: Migrasomes released by podocytes differ from exosomes as they have different content and mechanism of release. Compared to podocytes, renal tubular cells secrete markedly less migrasomes. Moreover, secretion of migrasomes by human or murine podocytes was strongly augmented during podocyte injuries induced by LPS, puromycin amino nucleoside (PAN), or a high concentration of glucose (HG). LPS, PAN, or HG-induced podocyte migrasome release, however, was blocked by Rac-1 inhibitor. Strikingly, a higher level of podocyte migrasomes in urine was detected in mice with PAN-nephropathy than in control mice. In fact, increased urinary migrasome number was detected earlier than elevated proteinuria during PAN-nephropathy, suggesting that urinary migrasomes are a more sensitive podocyte injury indicator than proteinuria. Increased urinary migrasome number was also detected in diabetic nephropathy patients with proteinuria level <5.5 g/day. Conclusions: Our findings reveal that podocytes release the “injury-related” migrasomes during migration and provide urinary podocyte migrasome as a potential diagnostic marker for early podocyte injury.