Exosomes released by human umbilical cord mesenchymal stem cells protect against cisplatin-induced renal oxidative stress and apoptosis in vivo and in vitro.
Exosomes released by human umbilical cord mesenchymal stem cells protect against cisplatin-induced renal oxidative stress and apoptosis in vivo and in vitro.
复制标题
人脐带间充质干细胞释放的外泌体在体内外可预防顺铂诱导的肾脏氧化应激和细胞凋亡
DOI：
10.1186/scrt194
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发表时间：
2013-04-25
影响因子：
7.5
通讯作者：
Qian H
中科院分区：
文献类型：
--
作者：
Zhou Y;Xu H;Xu W;Wang B;Wu H;Tao Y;Zhang B;Wang M;Mao F;Yan Y;Gao S;Gu H;Zhu W;Qian H
引言
应用骨髓间充质干细胞(MSCs)或分泌的微泡可促进急性肾损伤(AKI)的恢复。然而，潜在的作用和机制还没有被很好地理解。本研究旨在探讨人脐带间充质干细胞来源的外切体(hucMSC-EX)对顺铂所致肾毒性的保护作用。
方法
我们建立了顺铂诱导的AKI大鼠模型。顺铂处理24 h后，经肾被膜肾内注射hucMSC-ex，以人肺成纤维细胞(hFL-1)分泌的外切体(hFL-1-ex)为对照。顺铂给药后第5天处死动物。观察肾功能、肾组织学改变、肾小管细胞凋亡和增殖及氧化应激程度。体外培养大鼠肾小管上皮细胞(NRK-52E)，分别用不同浓度的顺铂处理NRK-52E细胞，6h后加或不加外切体。继续培养24 h，收集细胞进行免疫印迹、细胞凋亡和氧化应激程度检测。
结果
大鼠应用顺铂后，血尿素氮(BUN)、肌酐(Cr)水平升高，近端肾小管细胞凋亡、坏死，肾小管上皮细胞大量管型形成，氧化应激反应增强。而hucMSC-ex可显著降低顺铂诱导的AKI大鼠上述指标。在体外，单独用顺铂处理NRK-52E细胞后，NRK-52E细胞的凋亡率增加，氧化应激增加，p38丝裂原活化蛋白激酶(P38MAPK)通路激活，caspase3表达增加，细胞增殖下降，而hucMSCs+ex处理组的结果则相反。此外，还观察到hucMSC-ex通过激活细胞外信号调节激酶(ERK)1/2途径促进细胞增殖。
结论
本研究结果表明，hucMSC-ex可通过改善氧化应激和细胞凋亡，促进体内、外细胞增殖，修复顺铂诱导的大鼠AKI和NRK-52E细胞损伤。提示hucMSC-ex可作为治疗顺铂肾毒性的潜在工具。
Introduction
Administration of bone marrow mesenchymal stem cells (MSCs) or secreted microvesicles improves recovery from acute kidney injury (AKI). However, the potential roles and mechanisms are not well understood. In the current study, we focused on the protective effect of exosomes derived from human umbilical cord mesenchymal stem cells (hucMSC-ex) on cisplatin-induced nephrotoxicity in vivo and in vitro.
Methods
We constructed cisplatin-induced AKI rat models. At 24 h after treatment with cisplatin, hucMSC-ex were injected into the kidneys via the renal capsule; human lung fibroblast (HFL-1)-secreted exosomes (HFL-1-ex) were used as controls. All animals were killed at day 5 after administration of cisplatin. Renal function, histological changes, tubular apoptosis and proliferation, and degree of oxidative stress were evaluated. In vitro, rat renal tubular epithelial (NRK-52E) cells were treated with or without cisplatin and after 6 h treated with or without exosomes. Cells continued to be cultured for 24 h, and were then harvested for western blotting, apoptosis and detection of degree of oxidative stress.
Results
After administration of cisplatin, there was an increase in blood urea nitrogen (BUN) and creatinine (Cr) levels, apoptosis, necrosis of proximal kidney tubules and formation of abundant tubular protein casts and oxidative stress in rats. Cisplatin-induced AKI rats treated with hucMSC-ex, however, showed a significant reduction in all the above indexes. In vitro, treatment with cisplatin alone in NRK-52E cells resulted in an increase in the number of apoptotic cells, oxidative stress and activation of the p38 mitogen-activated protein kinase (p38MAPK) pathway followed by a rise in the expression of caspase 3, and a decrease in cell multiplication, while those results were reversed in the hucMSCs-ex-treated group. Furthermore, it was observed that hucMSC-ex promoted cell proliferation by activation of the extracellular-signal-regulated kinase (ERK)1/2 pathway.
Conclusions
The results in the present study indicate that hucMSC-ex can repair cisplatin-induced AKI in rats and NRK-52E cell injury by ameliorating oxidative stress and cell apoptosis, promoting cell proliferation in vivo and in vitro. This suggests that hucMSC-ex could be exploited as a potential therapeutic tool in cisplatin-induced nephrotoxicity.
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影响因子：
3.7
作者：
Bruno S;Grange C;Collino F;Deregibus MC;Cantaluppi V;Biancone L;Tetta C;Camussi G
通讯作者：
Camussi G
影响因子：
3.8
作者：
Khan, Rehan;Khan, Abdul Quaiyoom;Sultana, Sarwat
通讯作者：
Sultana, Sarwat
影响因子：
6.1
作者：
Gatti, Stefano;Bruno, Stefania;Camussi, Giovanni
通讯作者：
Camussi, Giovanni
影响因子：
3.4
作者：
Silici, Sibel;Ekmekcioglu, Oguz;Deniz, Kemal
通讯作者：
Deniz, Kemal
影响因子：
19.6
作者：
Tsuruya, K;Ninomiya, T;Iida, M
通讯作者：
Iida, M