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Khaled Hussein, Ahmed Ibrahim, Paul B Yu, Mohamed Al-Sayed Al-Shabrawey; Inhibition of BMP/SMAD pathway attenuates high glucose-induced retinal endothelial cell hyperpermeability . Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):1533.
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© ARVO (1962-2015); The Authors (2016-present)
Diabetic retinopathy (DR) is one of the most common complications of diabetes mellitus. Vision loss in DR principally occurs due to macular edema that results from breakdown of the blood-retinal barrier (BRB). Recently, we showed upregulation of BMP2/SMAD system in retina during diabetes and disruption of human retinal endothelial cells (hRECs) barrier function by BMP2. In the current study, we investigated the effect of inhibition of the BMP2/SMAD system on high glucose-induced retinal endothelial cell hyperpermeability.
Initially, hRECs were treated with 50ng/mL BMP2 for 24 Hours. A customized TaqMan® PCR array was used to detect the changes in mRNA expression of 32 genes implicated in retinal endothelial cell dysfunction such as NOX4, eNOS, SDF1, in addition to, different BMP receptors. The impact of inhibition of BMP/SMAD system using specific inhibitors of BMP receptor (LDN-212854) on high glucose-induced hRECs barrier function was evaluated by measuring the changes in trans-endothelial cell electrical resistance (TER) using the Electric Cell-Substrate Impedance Sensing (ECIS). Finally, since SMAD4 and NFκ-b are crucial in mediating most of BMP biological effect we examined their nuclear translocation in hRECs treated with BMP2 using western blot.
Treatment of hRECs with BMP2 induced significant upregulation of BMP2, TGFβ1, NOX4, eNOS, FLT1, and SDF1. Concerning the BMP receptors, BMPRII showed the highest upregulation followed by BMPRIA and ALK2. Meanwhile, pharmacological inhibition of BMP/SMAD system by LDN 212854 restored the TER in HG treated hRECs. Finally, treatment of hRECs with BMP2 induced nuclear translocation of both SMAD4 and NFκ-b.
Inhibition of BMP/SMAD system preserves the barrier function of hRECs treated with HG suggesting this pathway as a novel therapeutic target to prevent retinal endothelial barrier dysfunction in DR.
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