title: Pre-incubation with hucMSC-exosomes prevents cisplatin-induced nephrotoxicity by activating autophagy.
abstract: The administration of cisplatin is limited due to its nephrotoxic side effects, and prevention of this nephrotoxicity of cisplatin is difficult. Mesenchymal stem cell (MSC)-derived exosomes have been implicated as a novel therapeutic approach for tissue injury. In this study, we demonstrated that the pretreatment of human umbilical cord MSC-derived exosomes (hucMSC-Ex) can prevent the development of cisplatin-induced renal toxicity by activation of autophagy in vitro and in vivo.
  
  
  
  In vitro, rat renal tubular epithelial (NRK-52E) cells were pre-incubated with exosomes from hucMSC or HFL1 (human lung fibroblast cells; as control) for 30 min, and 3-methyladenine (an autophagic inhibitor) and rapamycin (an autophagic inducer) for 1 h before cisplatin treatment for 8 h, respectively. Cells were harvested for apoptosis assay, enzyme-linked immunosorbent assay (ELISA), Western blot, and quantitative real-time polymerase chain reaction (qRT-PCR). In vivo, we constructed cisplatin-induced acute kidney injury rat models. Prior to treatment with cisplatin for 0.5 h, hucMSC-Ex or HFL1-Ex were injected into the kidneys via the renal capsule. 3-methyladenine and rapamycin were injected under the kidney capsule before hucMSC-Ex. All animals were sacrificed at 3 days after cisplatin injection. Renal function, Luminex assay, tubular apoptosis and proliferation, and autophagy response were evaluated.
  
  
  
  hucMSC-Ex inhibited cisplatin-induced mitochondrial apoptosis and secretion of inflammatory cytokines in renal tubular epithelial cells in vitro. hucMSC-Ex increased the expression of the autophagic marker protein LC3B and the autophagy-related genes ATG5 and ATG7 in NRK-52E cells. Rapamycin mimicked the effects of hucMSC-Ex in protecting against cisplatin-induced renal injury, while the effects were abrogated by the autophagy inhibitor 3-methyladenine in the animals.
  
  
  
  Our findings indicate that the activation of autophagy induced by hucMSC-Ex can effectively relieve the nephrotoxicity of cisplatin. Therefore, pre-treatment of hucMSC-Ex may be a new method to improve the therapeutic effect of cisplatin.
authors.affiliation: Key Laboratory of Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, Jiangsu, 212013, People's Republic of China.|The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, People's Republic of China.
authors.forename: Bingying
authors.initials: B
authors.lastname: Wang
authors.affiliation: Key Laboratory of Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, Jiangsu, 212013, People's Republic of China.
authors.forename: Haoyuan
authors.initials: H
authors.lastname: Jia
authors.affiliation: Key Laboratory of Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, Jiangsu, 212013, People's Republic of China.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, Jiangsu, 212013, People's Republic of China.
authors.forename: Juanjuan
authors.initials: J
authors.lastname: Wang
authors.affiliation: Key Laboratory of Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, Jiangsu, 212013, People's Republic of China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Ji
authors.affiliation: The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, People's Republic of China.
authors.forename: Xueming
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Key Laboratory of Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, Jiangsu, 212013, People's Republic of China.
authors.forename: Yongmin
authors.initials: Y
authors.lastname: Yan
authors.affiliation: Key Laboratory of Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, Jiangsu, 212013, People's Republic of China.
authors.forename: Lei
authors.initials: L
authors.lastname: Yin
authors.affiliation: Key Laboratory of Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, Jiangsu, 212013, People's Republic of China.
authors.forename: Jing
authors.initials: J
authors.lastname: Yu
authors.affiliation: Key Laboratory of Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, Jiangsu, 212013, People's Republic of China. lstmmmlst@163.com.
authors.forename: Hui
authors.identifier: 0000-0002-0098-3196
authors.initials: H
authors.lastname: Qian
authors.affiliation: Key Laboratory of Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, Jiangsu, 212013, People's Republic of China. icls@ujs.edu.cn.
authors.forename: Wenrong
authors.initials: W
authors.lastname: Xu
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D000071187:Autophagy-Related Protein 5 / Q000235:genetics / Q000378:metabolism; D000071193:Autophagy-Related Protein 7 / Q000235:genetics / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D002945:Cisplatin / Q000037:antagonists & inhibitors* / Q000633:toxicity; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D055354:Exosomes / Q000737:chemistry / Q000637:transplantation*; D005260:Female; D005333:Fetus; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D009393:Nephritis / Q000139:chemically induced / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D061251:Primary Cell Culture; D051381:Rats; D017207:Rats, Sprague-Dawley; D020123:Sirolimus / Q000494:pharmacology; D014470:Umbilical Cord / Q000166:cytology / Q000378:metabolism
chemical_list: D000225:Adenine; D000071187:Autophagy-Related Protein 5; D000071193:Autophagy-Related Protein 7; D015415:Biomarkers; D002945:Cisplatin; D008869:Microtubule-Associated Proteins; D020123:Sirolimus; C545865:Atg5 protein, rat; C561242:Atg7 protein, rat; C526109:Anxa3 protein, rat; C025946:3-methyladenine
keywords: Autophagy; Cisplatin; Exosome; Human umbilical cord mesenchymal stem cell; Nephrotoxicity