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Antioxid Redox Signal. 2017 Nov 1;27(13):913-930. doi: 10.1089/ars.2016.6844. Epub 2017 Mar 17.

Exosomal MicroRNA-15a Transfer from the Pancreas Augments Diabetic Complications by Inducing Oxidative Stress.

Author information

1
1 University of Malaya Eye Research Centre, Department of Ophthalmology, University of Malaya , Kuala Lumpur, Malaysia .
2
2 Department of Pathology, Johns Hopkins University , Baltimore, Maryland.
3
3 School of Life Sciences, B.S. Abdur Rahman University , Chennai, India .
4
4 Department of Ophthalmology, Johns Hopkins University , Baltimore, Maryland.
5
5 Firefly, An Abcam Company , Cambridge, Massachusetts.

Abstract

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.

KEYWORDS:

diabetic vasculopathy; exosomes; microRNA; oxidative stress; pancreatic β-cells

PMID:
28173719
PMCID:
PMC5649125
DOI:
10.1089/ars.2016.6844
[Indexed for MEDLINE]
Free PMC Article

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