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Ward Fickweiler, Allen C Clermont, Nivetha Murugesan, Edward P Feener; Role of Akt in VEGF-, bradykinin-, and diabetes-induced retinal dysfunction and edema. Invest. Ophthalmol. Vis. Sci. 2014;55(13):2256.
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The VEGF and kallikrein kinin systems have been shown to mediate retinal dysfunction and edema. Both VEGF and bradykinin (BK) activate the serine/threonine-protein kinase Akt, which has been reported to mediate vascular hyperpermeability. The allosteric Akt-inhibitor MK2206 is currently in multiple phase II clinical trials in oncology. This study examines the effect of Akt inhibition by MK2206 on VEGF-, BK- and diabetes- induced retinal vascular permeability (RVP) and retinal thickness
Sprague-Dawley rats received intravitreal (IVT) injections of 2 µM BK, 10 ng VEGF, and 5 µM MK2206. Streptozotocin-induced diabetic rats received MK2206 for 2 weeks administered systemically using subcutaneously-implanted osmotic pumps. Retinal thickness, vessel tortuosity and vasodilation were measured using spectral domain optical coherence tomography. RVP was quantified using Evans-Blue dye permeation. Retinal proteomes were characterized using tandem mass spectrometry. Effects of BK, VEGF, and MK2206 on Akt phosphorylation were examined in primary cultures of Bovine Retinal Endothelial Cells (BREC)
BK and VEGF similarly increased retinal thickening by 46 µm (24.6%) vs. 39 µm (20.3%), respectively (p<0.01 vs. baseline) at 24 hours post IVT injection, and retinal thicknesses normalized at day 4 post-injection. Proteomic analysis identified a subset of plasma proteins in the retina that correlated with BK-induced retinal thickening, suggesting that plasma protein extravasation contributed to retinal edema. Retinal vessel diameters and tortuosity were significantly increased after IVT injections of BK or VEGF (p<0.05). Intravitreal co-injection of MK2206 reduced BK- and VEGF-induced retinal thickness by 65.9% and 56.8% respectively (p<0.05) and completely blocked BK-induced RVP (p<0.05). Systemically administered MK2206 normalized diabetes-induced RVP (p<0.05), without significantly affecting blood glucose, blood pressure, or body weight in diabetic rats. In vitro studies showed that both BK and VEGF increased Akt phosphorylation at Ser473 in BREC and these effects were inhibited by MK2206
Our data shows that Akt inhibition using MK2206 ameliorates the effects of VEGF, BK, and diabetes on retinal vascular leakage and retinal thickness in rats. These findings suggest that Akt inhibition may provide a therapeutic opportunity to block multiple pathways that may contribute to diabetic macular edema
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