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


METHODS
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.


CONCLUSIONS
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.
1 University of Malaya Eye Research Centre, Department of Ophthalmology, University of Malaya , Kuala Lumpur, Malaysia .
Tengku Ain
TA
Kamalden
2 Department of Pathology, Johns Hopkins University , Baltimore, Maryland.
Anne M
AM
Macgregor-Das
2 Department of Pathology, Johns Hopkins University , Baltimore, Maryland.|3 School of Life Sciences, B.S. Abdur Rahman University , Chennai, India .
Sangeetha Marimuthu
SM
Kannan
2 Department of Pathology, Johns Hopkins University , Baltimore, Maryland.
Brittany
B
Dunkerly-Eyring
1 University of Malaya Eye Research Centre, Department of Ophthalmology, University of Malaya , Kuala Lumpur, Malaysia .
Nurliza
N
Khaliddin
4 Department of Ophthalmology, Johns Hopkins University , Baltimore, Maryland.
Zhenhua
Z
Xu
5 Firefly, An Abcam Company , Cambridge, Massachusetts.
Anthony P
AP
Fusco
1 University of Malaya Eye Research Centre, Department of Ophthalmology, University of Malaya , Kuala Lumpur, Malaysia .
Syatirah Abu
SA
Yazib
1 University of Malaya Eye Research Centre, Department of Ophthalmology, University of Malaya , Kuala Lumpur, Malaysia .
Rhuen Chiou
RC
Chow
4 Department of Ophthalmology, Johns Hopkins University , Baltimore, Maryland.
Elia J
EJ
Duh
2 Department of Pathology, Johns Hopkins University , Baltimore, Maryland.
Marc K
MK
Halushka
2 Department of Pathology, Johns Hopkins University , Baltimore, Maryland.
Charles
C
Steenbergen
2 Department of Pathology, Johns Hopkins University , Baltimore, Maryland.
Samarjit
S
Das
D000328:Adult; D000818:Animals; D002460:Cell Line; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000235:genetics*; D003930:Diabetic Retinopathy / Q000097:blood / Q000235:genetics*; D004195:Disease Models, Animal; D055354:Exosomes / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000097:blood*; D008875:Middle Aged; D018384:Oxidative Stress; D051381:Rats; D015854:Up-Regulation
C505361:MIRN15 microRNA, human; D035683:MicroRNAs
diabetic vasculopathy; exosomes; microRNA; oxidative stress; pancreatic β-cells