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Human umbilical cord mesenchymal stem cell exosomes alleviate sepsis-associated acute kidney injury via regulating microRNA-146b expression

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Abstract

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.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (Grant 81871496), Zhenjiang Key Laboratory of High Technology Research on Exosomes Foundation and Transformation Application (Grant SS2018003), the Major Research Plan of Jiangsu Higher Education (Grant 15KJA320001), Jiangsu Province’s Major Project in Research and Development (Grant BE2016717), and Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).

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Correspondence to Hui Qian.

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Zhang, R., Zhu, Y., Li, Y. et al. Human umbilical cord mesenchymal stem cell exosomes alleviate sepsis-associated acute kidney injury via regulating microRNA-146b expression. Biotechnol Lett (2020). https://doi.org/10.1007/s10529-020-02831-2

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Keywords

  • AKI
  • Exosomes
  • microRNA-146b
  • NF-kappaB
  • Sepsis