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Rashidul Haque, Li He, Ashley Ngo, Samantha Gokhale, Madiha Aseem, Daniel Park; RAC1 regulates the expression of VEGF via targeting HIF-1alpha in ARPE-19 cells under hyperglycemic condition. Invest. Ophthalmol. Vis. Sci. 2018;59(9):2465.
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Upregulation of miR-21 in hyperglycemic retinal pigment epithelium (RPE) cells is responsible for the increased expression of vascular endothelial growth factor (VEGF), which is mediated via sprouty homolog (SPRY)1, Mothers against decapentaplegic homolog (SMAD) 7, and phosphatase and tensin homolog (PTEN) signaling, as shown in our previous publication (Haque R et al., Mol Vis. 2017, 23: 251-262). In this study, we examined the underlying role of Rho family small GTPase Rac1, as a potential intermediate, in the regulation of prorenin receptor (PRR)-mediated induction of VEGF expression via targeting hypoxia-inducible factor (HIF)-1alpha in a hyperglycemic condition.
PRR-mediated induction of HIF-1α and VEGF under a hyperglycemic condition (high glucose, 33mM) was studied by treating ARPE-19 cells with perindopril (10 µmol/l), which blocks angiotensin II-mediated signaling. Cells cultured in normal glucose (NG, 5.5 mM) were considered as the control. To examine the role of Rac1 in the regulation of HIF-1α and VEGF, ARPE-19 cells were transfected with a scramble negative control (Scr), PRR, or RAC1 siRNAs.
High glucose significantly induced the expression of PRR, RAC1, pERK (p44), HIF-1α, and VEGF as compared with the NG. However, blocking the expression of PRR significantly abolished the high glucose-induced expression of RAC1, HIF-1α, and VEGF, suggesting the involvement of PRR signaling in the regulation of RAC1 and VEGF. Also, silencing of RAC1 significantly attenuated the high glucose-induced expression of miR-21, pERK (p44), HIF-1α, and VEGF expression, indicative of the involvement of RAC1 in the regulation of HIF-1α and VEGF, which is mediated via miR-21 pathway.
We showed, for the first time, that RAC1 is crucial to activate miR-21, HIF-1, and VEGF in RPE cells under hyperglycemic condition. Therefore, RAC1 may serve as a potential therapeutic target for diabetes-induced retinal pathology.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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