Zhenjiang Key Laboratory of High Technology Research on Exosomes Foundation and Transformation Application, Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, 212013, Jiangsu, People's Republic of China.
Huai'an Maternity and Child Health Care Hospital, Huai'an, Jiangsu, People's Republic of China.
Biotechnol Lett. 2020 Apr;42(4):669-679. doi: 10.1007/s10529-020-02831-2. Epub 2020 Feb 11.
Human umbilical cord mesenchymal stem cell-derived exosomes (HucMSC-Ex) are a promising tool for the repair of acute kidney injury (AKI) caused by cisplatin and ischemia/reperfusion. However, the roles of hucMSC-Ex in sepsis-associated AKI repair and its mechanism are largely unknown. Hence, we constructed a sepsis model through cecal ligation and puncture (CLP), testing the benefits of hucMSC-Ex in the sepsis in terms of survival rate, serum renal markers levels, morphological changes and apoptosis. Immunohistochemistry staining and immunofluorescence assay were used to investigate the role of NF-κB activity in the repair of sepsis-associated AKI with hucMSC-Ex. HK-2 cells were transfected with microRNA-146b (miR-146b) mimics and inhibitors, respectively, and the regulatory effect of miR-146b on NF-κB activity was studied. We found that hucMSC-Ex treatment significantly decreased the serum creatinine (Cr) and blood urea nitrogen (BUN) levels, ameliorated the morphological damage and inhibited renal tubular cells apoptosis. More importantly, the survival rate at 72 h was 28% in CLP group and 45% in hucMSC-Ex group, respectively. Treatment with hucMSC-Ex improved survival in mice with sepsis. These effects of hucMSC-Ex were mediated by the inhibition of NF-κB activity and the lessening of pro-inflammatory response. Furthermore, hucMSC-Ex significantly increased miR-146b expression in kidney tissues. Conversely, interleukin (IL)-1 receptor-associated kinase (IRAK1) level, which is the target gene of miR-146b, clearly decreased in hucMSC-Ex group. In brief, this study showed that treatment with hucMSC-Ex decreased IRAK1 expression through the up-regulation of miR-146b level, led to the inhibition of NF-κB activity, and eventually alleviated sepsis-associated AKI and improved survival in mice with sepsis. HucMSC-Ex may be a novel therapeutic agent for the reduction of sepsis-associated AKI.
人脐带间充质干细胞来源的外泌体（HucMSC-Ex）是一种很有前途的工具，可用于修复顺铂和缺血/再灌注引起的急性肾损伤（AKI）。然而，hucMSC-Ex 在脓毒症相关 AKI 修复中的作用及其机制在很大程度上尚不清楚。因此，我们通过盲肠结扎和穿刺（CLP）构建了一个脓毒症模型，从存活率、血清肾标志物水平、形态变化和细胞凋亡等方面测试了 hucMSC-Ex 在脓毒症中的益处。免疫组织化学染色和免疫荧光分析用于研究 NF-κB 活性在 hucMSC-Ex 修复脓毒症相关 AKI 中的作用。HK-2 细胞分别转染 microRNA-146b（miR-146b）模拟物和抑制剂，研究 miR-146b 对 NF-κB 活性的调节作用。我们发现，hucMSC-Ex 治疗可显著降低血清肌酐（Cr）和血尿素氮（BUN）水平，改善形态损伤并抑制肾小管细胞凋亡。更重要的是，CLP 组 72 小时的存活率为 28%，hucMSC-Ex 组为 45%。hucMSC-Ex 治疗可改善脓毒症小鼠的存活率。hucMSC-Ex 的这些作用是通过抑制 NF-κB 活性和减轻促炎反应来介导的。此外，hucMSC-Ex 可显著增加肾脏组织中 miR-146b 的表达。相反，白细胞介素（IL）-1 受体相关激酶（IRAK1）水平，即 miR-146b 的靶基因，在 hucMSC-Ex 组中明显降低。简而言之，本研究表明，hucMSC-Ex 通过上调 miR-146b 水平降低 IRAK1 表达，导致 NF-κB 活性抑制，最终减轻脓毒症相关 AKI 并改善脓毒症小鼠的存活率。hucMSC-Ex 可能是一种用于减少脓毒症相关 AKI 的新型治疗剂。
