International Journal of Nanomedicine (May 2021)
Mesenchymal Stem Cells Attenuate Renal Fibrosis via Exosomes-Mediated Delivery of microRNA Let-7i-5p Antagomir
Abstract
Juan Jin,* Fengmei Qian,* Danna Zheng, Wenfang He, Jianguang Gong, Qiang He Department of Nephrology, Zhejiang Provincial People’s Hospital and Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, 310014, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jianguang Gong; Qiang HeDepartment of Nephrology, Zhejiang Provincial People’s Hospital and Affiliated People’s Hospital, Hangzhou Medical College, 158 Shangtang Road, Xiacheng District, Hangzhou, Zhejiang, 310014, People’s Republic of ChinaEmail [email protected]; [email protected]: Renal fibrosis is a chronic and progressive process affecting kidneys in chronic kidney disease (CKD). Mesenchymal stem cells-derived exosomes (MSCs-Exo) have been shown to alleviate renal fibrosis and injury, but the mechanism of MSCs-Exo-induced renal protection remains unknown.Methods: In this study, MSCs were transfected with let-7i-5p antagomir (anti-let-7i-5p), and then exosomes were isolated from the transfected MSCs to deliver anti-let-7i-5p oligonucleotides to inhibit the level of let-7i-5p in kidney tubular epithelial cells (NRK-52E).Results: In both NRK-52E cells stimulated by TGF-β 1 and the mouse kidneys after unilateral ureteral obstruction (UUO), we demonstrated increased level of let-7i-5p. In addition, MSCs-Exo can deliver anti-let-7i-5p to reduce the level of let-7i-5p in NRK-52E cells and increase the expression of its target gene TSC1. Moreover, exosomal anti-let-7i-5p reduced extracellular matrix (ECM) deposition and attenuated epithelial–mesenchymal transition (EMT) process in transforming growth factor beta 1 (TGF-β 1)-stimulated NRK-52E cells and in the kidneys of UUO-treated mice. Meanwhile, mice received exosomal anti-let-7i-5p displayed reduced renal fibrosis and improved kidney function when challenged with UUO. Furthermore, exosomal anti-let-7i-5p promoted the activation the tuberous sclerosis complex subunit 1/mammalian target of rapamycin (TSC1/mTOR) signaling pathway in vivo and in vitro.Conclusion: In conclusion, exosomal anti-let-7i-5p from MSCs exerts anti-fibrotic effects in TGF-β 1-induced fibrogenic responses in NRK52E cells in vitro as well as in UUO-induced renal fibrosis model in vivo. These results provided a novel perspective on improving renal fibrosis by MSCs-Exo.Keywords: chronic kidney disease, renal fibrosis, mesenchymal stem cells, exosomes and microRNAs
