外泌体治疗小鼠腹膜透析相关性腹膜纤维化的时效性和量效性研究  

Timeliness and dose-effectiveness of exosomes in the treatment of peritoneal dialysis-associated peritoneal fibrosis in mice

作　　者：汪晓月 喻芳 蔡青利 罗佳 陈娟 柏利华 陈佳 何娅妮 陈客宏 WANG Xiao-yue;YU Fang;CAI Qing-li;LUO Jia;CHEN Juan;BO Li-hua;CHEN Jia;HE Ya-ni;CHEN Ke-hong(Department of Nephrology,Army Specialty Medical Center,Chongqing 400042,China)

机构地区：[1]陆军军医大学大坪医院肾内科,重庆400042

出　　处：《中国血液净化》2023年第7期516-521,共6页Chinese Journal of Blood Purification

基　　金：重庆市在渝院士牵头科技创新引导专项(2022YSZX-JCX0007CSTB);重庆市科卫联合医学科技创新四大工程青年项目(2023QNXM007);重庆市技术创新与应用发展专项重点项目(cstc2019jscx-gksbX0024)。

摘　　要：目的探索不同剂量的骨髓间充质干细胞(bone marrow mesenchyml stem cell,BMSCs)来源的外泌体对腹膜透析腹膜纤维化的治疗效果,寻找BMSCs外泌体最佳治疗剂量和时机。方法建立高糖腹膜透析液诱导的腹膜纤维化小鼠模型,分为正常对照组、外泌体组、腹膜纤维化组和腹膜纤维化+外泌体组。外泌体组分别于6个时间点予以外泌体干预,并通过4个不同外泌体剂量来确定最佳治疗剂量及时机。结果高糖腹膜透析液诱导的腹膜纤维化模型小鼠从28d开始出现腹膜纤维化病理改变,并随模型建立时间的延长而加重,提示BMSCs外泌体治疗的干预时机可能是28d。在28d予以4个不同剂量的外泌体治疗,50μg/kg组和100μg/kg组与腹膜纤维化组相比腹膜厚度、纤维化标志物(Collagen-I)表达无显著性差异(t=0.540、1.031,P=0.705、0.360),但200μg/kg组和400μg/kg组与腹膜纤维化组相比腹膜纤维化显著改善(t=5.071、5.226,P=0.005、0.005),而200μg/kg组与400μg/kg相比无显著性差异(t=1.540,P=0.280)。结果提示外泌体治疗的最佳剂量为200μg/kg。进一步探索外泌体治疗时机,发现28d、35d分别进行外泌体干预均能明显减轻腹膜增厚(t=4.608、4.608,P=0.007、0.007),并且28d联合35d外泌体治疗相比单次治疗(28d,35d)减轻腹膜增厚效果更佳(t=5.730、5.730,P=0.003、0.003)。结果提示外泌体治疗小鼠腹膜纤维化在28d联合35d的治疗效果最佳。结论本研究发现BMSCs外泌体治疗小鼠腹膜纤维化的最佳时机为28d和35d,且最佳剂量为200μg/kg。Objective To investigate the therapeutic effect of different doses of exosomes derived from bone marrow mesenchymal stem cells(BMSCs)on peritoneal fibrosis,and to find out the optimal therapeutic dose and timing of BMSCs exosome therapy.Methods A mouse model of peritoneal fibrosis induced by high concentration of glucose in peritoneal dialysate was established and divided into the normal control group,exosome group,peritoneal fibrosis group and peritoneal fibrosis+exosome group.The exosome group was treated by giving exosomes at 6 time points and 4 different exosome doses to determine the optimal therapeutic dose and timing.Results Pathological changes of peritoneal fibrosis in the mouse model induced by high concentration of glucose in peritoneal dialysate were observed at the 28th day and became worse with prolongation of the treatment,suggesting that the BMSCs exosome therapy may be preferable from the 28th day.Administration of the exomes at the 28th day,peritoneal thickness and collagen I expression had no differences between the exomes 50μg/kg and 100μg/kg groups(t=0.540,P=0.705;t=1.031,P=0.360)but peritoneal fibrosis alleviated significantly in exomes 200μg/kg and 400μg/kg groups(t=5.071,P=0.005;t=5.226,P=0.005),as compared with those in the peritoneal fibrosis group.However,there was no significant difference in improvement of peritoneal fibrosis between exomes 200μg/kg group and 400μg/kg group(t=1.540,P=0.280).These results suggested that exomes 200μg/kg may be the optimal dosage of peritoneal fibrosis therapy.Further exploration of the timing of exosome therapy showed that peritoneal thickening could be significantly reduced by the exosome therapy at the 28th day or at the 35th day(t=4.608,P=0.007;t=4.608,P=0.007),and exosome therapy at the 28th day plus at the 35th day was more effective than the single treatment at the 28th day or at the 35th day(t=5.730,P=0.003;t=5.730,P=0.003).These results suggested that the optimal exosome therapy was given at the 28th day plus at the 35th day for mouse per

关 键 词：外泌体 腹膜透析 腹膜纤维化 时效分析 量效分析 

分 类 号：R459.5[医药卫生—治疗学]