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Abstract: SA-OR023

Exosome-Mediated miR-26a Treatment Attenuates Muscle Atrophy and Kidney Fibrosis in Diabetic Mice

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Zhang, Aiqing, Emory University, Atlanta, United States
  • Klein, Janet D., Emory University, Atlanta, Georgia, United States
  • Wang, Xiaonan H., Emory University, Atlanta, Georgia, United States
Background

The treatment of muscle wasting is well known to be accompanied by benefits in other organs. However, how the muscle communicates with these organs is less understood. Exosomes, natural carriers of many signal molecules including microRNA (miR), mediate organ to organ communication. We hypothesized that intramuscular injection of miR-26a would counteract both muscle wasting and renal fibrosis through exosome-mediated muscle-kidney crosstalk in diabetic mice.

Methods

We used an engineered exosome vector which contains an exosomal membrane protein gene - lysosomal-associated membrane protein 2b (Lamp2b) fused with kidney specific surface peptide [(KKEEE)3K] for kidney targeting delivery. Exosome encapsulated miR-26a (Exo/miR26) were generated in cultured skeletal muscle satellite cells, collected from conditioned media, and injected into the tibialis anterior muscle of diabetic mice. Diabetes mellitus was induced by low dose STZ injection (5-days). A NanoSight instrument was used to quantify exosomes. MiR deep sequencing and qPCR were used to identify microRNA expression. The In-Vivo Xtreme camera system was used to detect exosomes in vivo.

Results

miR-26a was decreased in skeletal muscle and kidney of diabetic mice. Diabetic serum enhanced secretion of miR-26a exosomes from cultured skeletal satellite cells and HEK293 kidney cells. The delivery of exogenous Exo/miR26a into muscle increased the levels of miR-26a in skeletal muscle and kidney, as well as increasing muscle cross-sectional area and decreasing diabetes-induced upregulation of atrogin-1 and MuRF1. Interestingly, renal fibrosis lesions were partially depressed, and α-SMA, connective tissue growth factor (CTGF), fibronectin and collagen1α were decreased in diabetic kidney with intramuscular injection of Exo/miR-26a. Blood urea nitrogen was decreased in diabetic mice treated with Exo/miR26a. Using fluorescent dye labeled Exo/miR26a, we found that the fluorescence intensity in kidney was linearly correlated with skeletal muscle.

Conclusion

overexpression of miR-26a in muscle prevents diabetes-induced muscle loss and attenuates renal fibrosis via exosome-mediated muscle-kidney crosstalk. These results could provide new approaches for developing therapeutic strategies for kidney diseases with muscle wasting.

Funding

  • Other NIH Support