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M. Matsumoto, K. Suzuma, T. Maki, N. Miyamura, H. Kinoshita, T. Kitaoka; Succinate as a Retinal Angiogenic Factor in Proliferative Diabetic Retinopathy. Invest. Ophthalmol. Vis. Sci. 2010;51(13):5637.
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Although vascular endothelial growth factor (VEGF) is a primary mediator of retinal angiogenesis, VEGF inhibition alone is insufficient to prevent retinal neovascularization. Hence, it is postulated that there are other potent ischemia-induced angiogenic factors. There is a report that succinate accumulates in the hypoxic retina of rodents and, via its cognate receptor G protein-coupled receptor-91 (GPR91), is a potent mediator of vessel growth in the settings of both normal retinal development and proliferative ischemic retinopathy. But there is no report which examine the level of succinate in human vitreous fluid and aqueous humor.
We measured the level of succinate in the vitreous fluid of 46 eyes in 41 proliferative diabetic retinopathy (PDR) patients by selected ion monitoring mode of liquid chromatography-mass spectrometry. The 46 eyes were divided into two groups: active retinopathy group (APDR group) consisted of 23 eyes; quiescent retinopathy group (QPDR group) consisted of 23 eyes. The 21 eyes of 21 epiretinal membrane patients (ERM group) were selected as a control group. We measured VEGF levels in the vitreous fluid with enzyme-linked immunosorbent assay. And we confirmed the existence of the succinate receptor GPR91 in rat retina, and human fibrovascular membrane surgically excised from PDR patients by immnohistochemistry.
The mean vitreous succinate levels were 2.91µM in APDR group, 1.62µM in ERM group, and 1.15µM in QPDR group. There was a significant difference between APDR group and QPDR group (P< 0.05). The mean VEGF level in APDR group was also significantly higher than that in QPDR group (1622.2 vs. 76.7 pg per milliliter, P<0.001). Immnoreactivity of the succinate receptor GPR91 was observed in the ganglion cell layer in rat retina, and the surface of fibrovascular membrane.
Our data suggest that succinate may be an ischemia-induced angiogenic factor during retinal angiogenesis in proliferative diabetic retinopathy like VEGF.
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