Exogenous miR-29a Attenuates Muscle Atrophy and Kidney Fibrosis in UUO Mice

Our previous study found that miR-29a was decreased in skeletal muscle of mice with renal disease. However, the cause of decreasing miR-29a and the influence other organs is less known. We hypothesized that adeno-associated virus (AAV)-mediated overexpressing miR-29a would counteract unilateral ureteral obstruction (UUO)-induced muscle wasting and renal fibrosis via muscle-kidney crosstalk. The expression of miR-29a was decreased in skeletal muscle and kidney of UUO mice. Serum from UUO mice enhanced secretion of exosome-encapsulated miR-29a from cultured skeletal muscle satellite cells and HEK293 renal cells. This was confirmed by qPCR and microRNA deep sequencing in serum exosomes of mice with obstructed ureters. We generated a recombinant adeno-associated virus (AAV-miR29a) to overexpress miR-29a and injected it into the tibialis anterior (TA) muscle of UUO mice for 14-days. The AAV-miR-29a decreased UUO-induced upregulation of YY1 and myostatin in skeletal muscle. In addition, renal fibrosis was partially depressed in the UUO mice with intramuscular transduction with AAV-miR-29a. We found that TGF, alpha-smooth muscle actin (SMA), fibronectin, collagen 1A1 and 4A1 were increased in the kidney of UUO mice, overexpressing by AAV-miR-29a reversed these changes. When we used AAV-GFP to trace the AAV route in vivo we found that fluorescence was significantly visible in both injected and un-injected muscle and in kidneys. We conclude that intramuscular injection of AAV-miR-29a not only ameliorates skeletal protein metabolism, but also attenuates UUO-induced kidney fibrosis by down-regulating TGF- pathway cascade proteins and extracellular matrix components. Funding Statement: Research reported in this publication was supported by grants from the National Natural Science Foundation of China (Nos. 81700650, 81700618, 31772690), and the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) of the National Institutes of Health under Award Number R01 AR060268 and American Heart Association Discover and Innovation Grants (17IBDG33780000) to X.H.W. and the Natural Science Foundation of Jiangsu Province (BK20181487), China Young Nephrologist Research Project, and Southeast University High Level Thesis Project to B. W. Declaration of Interests: The authors state no conflicts of interest. Ethics Approval Statement: These experiments were approved by the Emory University IACUC (protocol 141-2008).