Theranostics 2019; 9(7):1864-1877. doi:10.7150/thno.29579 This issue Cite

Research Paper

miR-26a Limits Muscle Wasting and Cardiac Fibrosis through Exosome-Mediated microRNA Transfer in Chronic Kidney Disease

Bin Wang1,3*, Aiqing Zhang2,3*, Haidong Wang3,4, Janet D. Klein3, Lin Tan5, Ze-Mu Wang6, Jie Du7, Nawazish Naqvi5, Bi-Cheng Liu1, Xiaonan H. Wang3✉

1. Institute of Nephrology, Zhong Da Hospital, Southeast University, Nanjing, Jiangsu, 210009, China
2. Department of Pediatric Nephrology, the Second Affiliated Hospital of Nanjing Medical University, Nanjing, 210003, China
3. Renal Division, Department of Medicine, Emory University, Atlanta, GA 30322, USA
4. College of Animal Science and Veterinary Medicine, Shanxi Agricultural University, Taigu, Shanxi, 030801, China
5. Division of Cardiology, Department of Medicine, Emory University, Atlanta, GA 30322, USA
6. Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
7. The Key Laboratory of Remodeling-related Cardiovascular Diseases, Beijing Anzhen Hospital Affiliated to Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing 100029, China
*Both authors contributed equally to this work.

Citation:
Wang B, Zhang A, Wang H, Klein JD, Tan L, Wang ZM, Du J, Naqvi N, Liu BC, Wang XH. miR-26a Limits Muscle Wasting and Cardiac Fibrosis through Exosome-Mediated microRNA Transfer in Chronic Kidney Disease. Theranostics 2019; 9(7):1864-1877. doi:10.7150/thno.29579. https://www.thno.org/v09p1864.htm
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Abstract

Graphic abstract

Uremic cardiomyopathy and muscle atrophy are associated with insulin resistance and contribute to chronic kidney disease (CKD)-induced morbidity and mortality. We hypothesized that restoration of miR-26a levels would enhance exosome-mediated microRNA transfer to improve muscle wasting and cardiomyopathy that occur in CKD.

Methods: Using next generation sequencing and qPCR, we found that CKD mice had a decreased level of miR-26a in heart and skeletal muscle. We engineered an exosome vector that contained Lamp2b, an exosomal membrane protein gene fused with a muscle-specific surface peptide that targets muscle delivery. We transfected this vector into muscle satellite cells and then transduced these cells with adenovirus that expresses miR-26a to produce exosomes encapsulated miR-26a (Exo/miR-26a). Exo/miR-26a was injected once per week for 8 weeks into the tibialis anterior (TA) muscle of 5/6 nephrectomized CKD mice.

Results: Treatment with Exo/miR-26a resulted in increased expression of miR-26a in skeletal muscle and heart. Overexpression of miR-26a increased the skeletal muscle cross-sectional area, decreased the upregulation of FBXO32/atrogin-1 and TRIM63/MuRF1 and depressed cardiac fibrosis lesions. In the hearts of CKD mice, FoxO1 was activated, and connective tissue growth factor, fibronectin and collagen type I alpha 1 were increased. These responses were blunted by injection of Exo/miR-26a. Echocardiograms showed that cardiac function was improved in CKD mice treated with Exo/miR-26a.

Conclusion: Overexpression of miR-26a in muscle prevented CKD-induced muscle wasting and attenuated cardiomyopathy via exosome-mediated miR-26a transfer. These results suggest possible therapeutic strategies for using exosome delivery of miR-26a to treat complications of CKD.

Keywords: uremic cardiomyopathy, muscle wasting, insulin resistance, surface peptide, Lamp2b


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APA
Wang, B., Zhang, A., Wang, H., Klein, J.D., Tan, L., Wang, Z.M., Du, J., Naqvi, N., Liu, B.C., Wang, X.H. (2019). miR-26a Limits Muscle Wasting and Cardiac Fibrosis through Exosome-Mediated microRNA Transfer in Chronic Kidney Disease. Theranostics, 9(7), 1864-1877. https://doi.org/10.7150/thno.29579.

ACS
Wang, B.; Zhang, A.; Wang, H.; Klein, J.D.; Tan, L.; Wang, Z.M.; Du, J.; Naqvi, N.; Liu, B.C.; Wang, X.H. miR-26a Limits Muscle Wasting and Cardiac Fibrosis through Exosome-Mediated microRNA Transfer in Chronic Kidney Disease. Theranostics 2019, 9 (7), 1864-1877. DOI: 10.7150/thno.29579.

NLM
Wang B, Zhang A, Wang H, Klein JD, Tan L, Wang ZM, Du J, Naqvi N, Liu BC, Wang XH. miR-26a Limits Muscle Wasting and Cardiac Fibrosis through Exosome-Mediated microRNA Transfer in Chronic Kidney Disease. Theranostics 2019; 9(7):1864-1877. doi:10.7150/thno.29579. https://www.thno.org/v09p1864.htm

CSE
Wang B, Zhang A, Wang H, Klein JD, Tan L, Wang ZM, Du J, Naqvi N, Liu BC, Wang XH. 2019. miR-26a Limits Muscle Wasting and Cardiac Fibrosis through Exosome-Mediated microRNA Transfer in Chronic Kidney Disease. Theranostics. 9(7):1864-1877.

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