Satellite cell-derived exosome-mediated delivery of microRNA-23a/27a/26a cluster ameliorates the renal tubulointerstitial fibrosis in mouse diabetic nephropathy  

作　　者：Jia-ling Ji Hui-min Shi Zuo-lin Li Ran Jin Gao-ting Qu Hui Zheng E.Wang Yun-yang Qiao Xing-yue Li Ling Ding Da-fa Ding Liu-cheng Ding Wei-hua Gan Bin Wang Ai-qing Zhang 

机构地区：[1]Department of Pediatric Nephrology,the Second Affiliated Hospital of Nanjing Medical University,Nanjing,210003,China [2]Institute of Nephrology,Zhong Da Hospital,Southeast University School of Medicine,Nanjing,210009,China [3]Department of Pediatrics,the Fourth Affiliated Hospital of Nanjing Medical University,Nanjing,210031,China [4]Department of Endocrinology,the Second Affiliated Hospital of Nanjing Medical University,Nanjing,210003,China [5]Department of Urology,the Second Affiliated Hospital of Nanjing Medical University,Nanjing,210003,China

出　　处：《Acta Pharmacologica Sinica》2023年第12期2455-2468,共14页中国药理学报（英文版）

基　　金：the National Natural Science Foundation of China(No.81970664,82000648,82070735);the Natural Science Foundation of Jiangsu Province(No.BK20211385,BK20200363);the 789 Outstanding Talent Program of the Second Affiliated Hospital of Nanjing Medical University(No.789ZYRC202080119,789ZYRC202090251);the Science and Technology Development Foundation of Nanjing Medical University(No.NMUB2020049);the Fundamental Research Funds for the Central Universities(No.2242023K40046).

摘　　要：Renal tubulointerstitial fibrosis(TIF)is considered as the final convergent pathway of diabetic nephropathy(DN)without effective therapies currently.MiRNAs play a key role in fibrotic diseases and become promising therapeutic targets for kidney diseases,while miRNA clusters,formed by the cluster arrangement of miRNAs on chromosomes,can regulate diverse biological functions alone or synergistically.In this study,we developed clustered miR-23a/27a/26a-loaded skeletal muscle satellite cells–derived exosomes(Exos)engineered with RVG peptide,and investigated their therapeutic efficacy in a murine model of DN.Firstly,we showed that miR-23a-3p,miR-26a-5p and miR-27a-3p were markedly decreased in serum samples of DN patients using miRNA sequencing.Meanwhile,we confirmed that miR-23a-3p,miR-26a-5p and miR-27a-3p were primarily located in proximal renal tubules and highly negatively correlated with TIF in db/db mice at 20 weeks of age.We then engineered RVG-miR-23a/27a/26a cluster loaded Exos derived from muscle satellite cells,which not only enhanced the stability of miR-23a/27a/26a cluster,but also efficiently delivered more miR-23a/27a/26a cluster homing to the injured kidney.More importantly,administration of RVG-miR-23a/27a/26a-Exos(100μg,i.v.,once a week for 8 weeks)significantly ameliorated tubular injury and TIF in db/db mice at 20 weeks of age.We revealed that miR-23a/27a/26a-Exos enhanced antifibrotic effects by repressing miRNA cluster-targeting Lpp simultaneously,as well as miR-27a-3p-targeting Zbtb20 and miR-26a-5p-targeting Klhl42,respectively.Knockdown of Lpp by injection of AAV-Lpp-RNAi effectively ameliorated the progression of TIF in DN mice.Taken together,we established a novel kidney-targeting Exo-based delivery system by manipulating the miRNA-23a/27a/26a cluster to ameliorate TIF in DN,thus providing a promising therapeutic strategy for DN.

关 键 词：diabetic nephropathy tubulointerstitial fibrosis skeletal muscle satellite cell EXOSOMES miR-23a/27a/26a cluster LPP Zbtb20 Klhl42 

分 类 号：R285.5[医药卫生—中药学]