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Youde Jiang, Jena Steinle; IGFBP-3 Regulates VEGF through PKCzeta in retinal endothelial cells cultured in high glucose. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):5177.
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© ARVO (1962-2015); The Authors (2016-present)
Since vascular endothelial cells growth factor (VEGF) is key to diabetic macular edema and can be regulated by insulin-like growth factor binding protein 3 (IGFBP-3), we determined the cellular signaling by which IGFBP-3 can reduce VEGF levels in retinal endothelial cells cultured in both normal and high glucose.
Primary retinal endothelial cells were cultured in normal (5mM) or high glucose (25mM) with some cells transfected with a mutant IGFBP-3 that does not bind IGF-1. Additional cells were treated with recombinant endothelial nitric oxide synthase (eNOS) or protein kinase C zeta (PKCz) following to transfection with mutant IGFBP-3 to determine the role of eNOS and PKCz in the regulation of VEGF.
VEGF, eNOS and PKCz are all increased in retinal endothelial cells cultured in high glucose, which were reduced by treatment with mutant IGFBP-3. When cells in high glucose were treated with IGFBP-3 and recombinant eNOS, eNOS significantly increased both the phosphorylation of PKCz and VEGF levels, which were reduced by IGFBP-3 transfection. Similar results were obtained in cells treated with IGFBP-3 and recombinant PKCz.
These data demonstrate that VEGF is regulated by IGFBP-3 in vascular cells cultured in high glucose. Furthermore, IGFBP-3 significantly reduces eNOS and PKCz to regulate VEGF. Taken together, this study provides a potential novel signaling pathway to allow for development of treatments for macular edema, in addition to the reduction in VEGF. Targeting upstream signaling pathways may also reduce VEGF-initiated responses in retinal endothelial cells.
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