Mesenchymal stem cells (MSCs) represent a promising treatment option for acute kidney injury (AKI). The main drawbacks of MSCs therapy, including the lack of specific homing after systemic infusion and early cell death in the inflammatory microenvironment, directly affect the therapeutic efficacy of MSCs. Erythropoietin (EPO)-preconditioning of MSCs promotes their therapeutic effect, however, the underlying mechanism remains unknown. In this study, we sought to investigate the efficacy and mechanism of EPO in bone marrow derived mesenchymal stem cells (BMSCs) for AKI treatment. We found that incubation of BMSCs with ischemia/reperfusion(I/R)-induced AKI kidney homogenate supernatant (KHS) caused apoptosis in BMSCs, which was decreased by EPO pretreatment, indicating that EPO protected the cells from apoptosis. Further, we showed that EPO up-regulated silent information regulator 1 (SIRT1) and Bcl-2 expression and down-regulated p53 expression. This effect was partially reversed by SIRT1 siRNA intervention. The anti-apoptotic effect of EPO in pretreated BMSCs may be mediated through the SIRT1 pathway. In a rat AKI model, 24 h after intravenous infusion, GFP-BMSCs were predominantly located in the lungs. However, EPO pretreatment reduced the lung entrapment of BMSCs and increased their distribution in the target organs. AKI rats infused with EPO-BMSCs had significantly lower levels of serum IL-1β and TNF-α, and a significantly higher level of IL-10 as compared to rats infused with untreated BMSCs. The administration of EPO-BMSCs after reperfusion reduced serum creatinine, blood urea nitrogen, and pathological scores in I/R-AKI rats more effectively than BMSCs treatment did. Our data suggest that EPO pretreatment enhances the efficacy of BMSCs to improve the renal function and pathological presentation of I/R-AKI rats.

中文翻译：

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促红细胞生成素预处理的骨髓源间充质干细胞促进急性肾损伤的修复

间充质干细胞（MSCs）代表急性肾损伤（AKI）的有前途的治疗选择。MSCs治疗的主要缺点包括全身输注后缺乏特异性归巢和炎性微环境中早期细胞死亡，直接影响了MSCs的治疗功效。MSC的促红细胞生成素（EPO）预处理可促进其治疗作用，但是其潜在机制仍然未知。在这项研究中，我们试图研究EPO在骨髓来源的间充质干细胞（BMSCs）用于AKI治疗中的功效和机制。我们发现与缺血/再灌注（I / R）诱导的AKI肾脏匀浆上清液（KHS）一起孵育BMSCs会导致BMSCs凋亡，EPO预处理可以降低凋亡，表明EPO保护细胞免受凋亡。进一步，我们发现EPO上调沉默信息调节因子1（SIRT1）和Bcl-2的表达而下调p53的表达。SIRT1 siRNA干预可部分逆转此效应。EPO在预处理的BMSC中的抗凋亡作用可能是通过SIRT1途径介导的。在大鼠AKI模型中，静脉输注24小时后，GFP-BMSCs主要位于肺中。但是，EPO预处理减少了BMSCs的肺部包埋并增加了它们在靶器官中的分布。与注入未经处理的BMSC的大鼠相比，注入EPO-BMSC的AKI大鼠的血清IL-1β和TNF-α的水平明显较低，而IL-10的水平则明显较高。再灌注后给予EPO-BMSC可降低血清肌酐，血尿素氮，I / R-AKI大鼠的病理学和病理学评分比BMSCs治疗更有效。我们的数据表明，EPO预处理可增强BMSC的功效，以改善I / R-AKI大鼠的肾功能和病理表现。