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Vision Res
2017[Oct]; 139
(?): 23-29
PMID28774775
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Hyperglycemia is a significant risk factor for diabetic retinopathy and induces
multiple biochemical changes, including inflammation and endothelial dysfunction
in the retina. Alterations in microRNA expression have been implicated in the
pathological responses of diabetic retinopathy and the manipulation of microRNA
may provide powerful strategy for therapeutics. Among the predicted targets of
miR-15a and -16 are TGF-beta3, SMAD2/3, and VEGF, all of which are known to play
a role in vascular endothelial functions. The purpose of this study was to
investigate the hypothesis that miR-15a/16 inhibits TGF-beta3/VEGF signaling to
maintain retinal endothelial cell barrier protein levels. Human primary retinal
endothelial cells (REC) were maintained in normal (5mM) glucose or transferred to
high glucose medium (25mM) for 3days. REC were transfected with miRNA mimics
(hsa-miR-15a-5p and -16-5p). Retinal lysates from miR-15a-transgenic mice were
also analyzed. We demonstrated that overexpression of miR-15a/16 resulted in
decreased TGF-beta3 signaling and VEGF levels in cultured REC grown in high
glucose conditions. In addition, the levels of tight junction proteins, zonula
occludens-1 (ZO-1) and occludin, were elevated in REC following overexpression of
miR-15a and -16. Overexpression of miR-15a and -16 played a role in reducing
cellular permeability through inhibition of VEGF signaling in REC cultured under
high glucose conditions. Using miR-15a-transgenic mice, we demonstrated the
regulatory role of miR-15a on TGF-beta3 signaling and tight junction proteins in
vivo. Our outcomes suggest that miR-15a/16 maintain the retinal endothelial cell
barrier by reducing TGFbeta3/VEGF signaling and increasing levels of key tight
junction proteins.
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