title: Exosomes released by human umbilical cord mesenchymal stem cells protect against cisplatin-induced renal oxidative stress and apoptosis in vivo and in vitro.
abstract: BACKGROUND
  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.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhou
authors.forename: Huitao
authors.initials: H
authors.lastname: Xu
authors.forename: Wenrong
authors.initials: W
authors.lastname: Xu
authors.forename: Bingying
authors.initials: B
authors.lastname: Wang
authors.forename: Huiyi
authors.initials: H
authors.lastname: Wu
authors.forename: Yang
authors.initials: Y
authors.lastname: Tao
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.forename: Mei
authors.initials: M
authors.lastname: Wang
authors.forename: Fei
authors.initials: F
authors.lastname: Mao
authors.forename: Yongmin
authors.initials: Y
authors.lastname: Yan
authors.forename: Shuo
authors.initials: S
authors.lastname: Gao
authors.forename: Hongbing
authors.initials: H
authors.lastname: Gu
authors.forename: Wei
authors.initials: W
authors.lastname: Zhu
authors.forename: Hui
authors.initials: H
authors.lastname: Qian
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced / Q000473:pathology / Q000628:therapy; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D002945:Cisplatin / Q000633:toxicity*; D055354:Exosomes / Q000378:metabolism*; D005260:Female; D006801:Humans; D007684:Kidney Tubules / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014183:Transplantation, Heterologous; D014470:Umbilical Cord / Q000166:cytology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D048051:p38 Mitogen-Activated Protein Kinases; D053148:Caspase 3; D002945:Cisplatin