Abstract
BackgroundThe 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.MethodsIn 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.ResultshucMSC-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.ConclusionsOur 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.
Highlights
The administration of cisplatin is limited due to its nephrotoxic side effects, and prevention of this nephrotoxicity of cisplatin is difficult
Our findings indicate that Human umbilical cord-derived mesenchymal stem cell (hucMSC)-Ex promoted autophagy in renal tubule epithelial cells and kidney tissues by cisplatin induced through the inhibition of mammalian target of rapamycin (mTOR), alleviating cell apoptosis and inflammatory response in the early stages
The results of enzyme-linked immunosorbent assay (ELISA) showed that, compared to the phosphate-buffered saline (PBS) group, tumor necrosis factor (TNF)-α levels decreased in the hucMSC-Ex group but were restored in the hucMSC-Ex + 3MA group (Fig. 4c) (P < 0.05). These results demonstrated that the activation of autophagy by hucMSCEx may contribute to its preventive effects on cisplatininduced apoptosis and the inflammatory response in vitro
Summary
The administration of cisplatin is limited due to its nephrotoxic side effects, and prevention of this nephrotoxicity of cisplatin is difficult. 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. Many studies have revealed that mesenchymal stem cell (MSC)-derived exosomes or microvesicles can promote tissue regeneration. MVs from human bone marrow-derived MSCs contribute to favor functional and morphological recovery in rodent models of acute kidney injury (AKI) induced by glycerol [7], ischemia/reperfusion [8], and cisplatin [9]. Our previous works indicate that human umbilical cord-derived MSCs (hucMSCs) improve the recovery of ischemia/reperfusion-induced rat renal injury via anti-apoptotic and anti-inflammatory mechanisms [10,11,12]. All the above studies show that hucMSC-Ex can improve the tissue injury It is unknown whether hucMSC-Ex administration before injury can prevent kidney damage in the early stages
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