TY - JOUR
T1 - Exosomal MicroRNA-15a Transfer from the Pancreas Augments Diabetic Complications by Inducing Oxidative Stress
AU - Kamalden, Tengku Ain
AU - Macgregor-Das, Anne M.
AU - Kannan, Sangeetha Marimuthu
AU - Dunkerly-Eyring, Brittany
AU - Khaliddin, Nurliza
AU - Xu, Zhenhua
AU - Fusco, Anthony P.
AU - Yazib, Syatirah Abu
AU - Chow, Rhuen Chiou
AU - Duh, Elia J.
AU - Halushka, Marc K.
AU - Steenbergen, Charles
AU - Das, Samarjit
N1 - Funding Information:
The authors thank the JHU-UMD Diabetes Research Center and Dr. Mehboob Hussain, Director, Cell Biology Core of Diabetes Research Center of The Johns Hopkins Hospital, for kindly providing the INS-1 cell lines. They thank Drs. Kenneth W. Witwer and Dillion Muth (Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD) for their generous advice on the Nanoparticle Tracking Analysis using NanoSight. The authors also thank Astrid Limb (Institute of Ophthalmology, UCL, London, UK) for providing the MIO-M1 and Dr. Vijay Sarthy from North-western University Feinberg School of Medicine (Chicago, IL) for providing rMC-1 cells. This work was supported by grants from the Ministry of Education, Malaysia (High Impact Research MoE Grant No. H-20001-00-E000056), and University of Malaya (Grant Nos. RP006B-13HTM and RP033-14HTM), the National Institutes of Health HL39752 (C.S.), American Heart Association: 14SDG18890049 (S.D.), and Firefly Bio-Works, Inc., Firefly Frontiers Grant (S.D.). B.D. gratefully acknowledges support from the Sister Alma McNicholas Fund from the Notre Dame of Maryland University. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the article.
Publisher Copyright:
© Copyright 2017, Mary Ann Liebert, Inc. 2017.
PY - 2017/11/1
Y1 - 2017/11/1
N2 - Aims: MicroRNAs (miRNAs), one type of noncoding RNA, modulate post-transcriptional gene expression in various pathogenic pathways in type 2 diabetes (T2D). Currently, little is known about how miRNAs influence disease pathogenesis by targeting cells at a distance. The purpose of this study was to investigate the role of exosomal miRNAs during T2D. Results: We show that miR-15a is increased in the plasma of diabetic patients, correlating with disease severity. miR-15 plays an important role in insulin production in pancreatic β-cells. By culturing rat pancreatic β-cells (INS-1) cells in high-glucose media, we identified a source of increased miR-15a in the blood as exosomes secreted by pancreatic β-cells. We postulate that miR-15a, produced in pancreatic β-cells, can enter the bloodstream and contribute to retinal injury. miR-15a overexpression in Müller cells can be induced by exposing Müller cells to exosomes derived from INS-1 cells under high-glucose conditions and results in oxidative stress by targeting Akt3, which leads to apoptotic cell death. The in vivo relevance of these findings is supported by results from high-fat diet and pancreatic β-cell-specific miR-15a-/- mice. Innovation: This study highlights an important and underappreciated mechanism of remote cell-cell communication (exosomal transfer of miRNA) and its influence on the development of T2D complications. Conclusion: Our findings suggest that circulating miR-15a contributes to the pathogenesis of diabetes and supports the concept that miRNAs released by one cell type can travel through the circulation and play a role in disease progression via their transfer to different cell types, inducing oxidative stress and cell injury. Antioxid. Redox Signal. 27, 913-930.
AB - Aims: MicroRNAs (miRNAs), one type of noncoding RNA, modulate post-transcriptional gene expression in various pathogenic pathways in type 2 diabetes (T2D). Currently, little is known about how miRNAs influence disease pathogenesis by targeting cells at a distance. The purpose of this study was to investigate the role of exosomal miRNAs during T2D. Results: We show that miR-15a is increased in the plasma of diabetic patients, correlating with disease severity. miR-15 plays an important role in insulin production in pancreatic β-cells. By culturing rat pancreatic β-cells (INS-1) cells in high-glucose media, we identified a source of increased miR-15a in the blood as exosomes secreted by pancreatic β-cells. We postulate that miR-15a, produced in pancreatic β-cells, can enter the bloodstream and contribute to retinal injury. miR-15a overexpression in Müller cells can be induced by exposing Müller cells to exosomes derived from INS-1 cells under high-glucose conditions and results in oxidative stress by targeting Akt3, which leads to apoptotic cell death. The in vivo relevance of these findings is supported by results from high-fat diet and pancreatic β-cell-specific miR-15a-/- mice. Innovation: This study highlights an important and underappreciated mechanism of remote cell-cell communication (exosomal transfer of miRNA) and its influence on the development of T2D complications. Conclusion: Our findings suggest that circulating miR-15a contributes to the pathogenesis of diabetes and supports the concept that miRNAs released by one cell type can travel through the circulation and play a role in disease progression via their transfer to different cell types, inducing oxidative stress and cell injury. Antioxid. Redox Signal. 27, 913-930.
KW - Diabetic vasculopathy
KW - Exosomes
KW - MicroRNA
KW - Oxidative stress
KW - Pancreatic β-cells
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U2 - 10.1089/ars.2016.6844
DO - 10.1089/ars.2016.6844
M3 - Article
C2 - 28173719
AN - SCOPUS:85030219509
SN - 1523-0864
VL - 27
SP - 913
EP - 930
JO - Antioxidants and Redox Signaling
JF - Antioxidants and Redox Signaling
IS - 13
ER -