DiaComp Funded Abstracts
Program Application Abstract
The effect of VEGF and the kallikrein kinin system upon retinal neuronal signaling
(Joslin Diabetes Center - Boston)
Summer Student Program
Diabetic macular edema (DME) is a sight-threatening condition currently treated with anti- vascular endothelial growth factor (VEGF) therapy, however about 50% of patients are unresponsive to this treatment. VEGF has been shown to activate the kallikrein-kinin system (KKS), which is mediated through bradykinin (BK) and contributes to retinal thickening. In addition to their vascular effects, both VEGF and BK cause an increase in amplitude of the electroretinogram (ERG), suggesting that these factors have neuronal effects that may contribute to vision loss. Since a nitric oxide (NO) agonist has been shown to cause a similar increase in ERG amplitude, and elevated glutamate in the diabetic eye may activate nitric oxide synthase (NOS), we hypothesized that the neuro-retinal effects induced by VEGF/BK are mediated through glutamate and/or nitric oxide signaling. First, we investigated the effects of administering VEGF and BK on glutamate release in both rat astrocyte cell culture and in vivo via intravitreal (IVT) injection in rat eyes. We then determined the effect of the glutamate NMDA receptor antagonist MK-801 on ERG as well the effect of the NOS inhibitor L-NAME on both retinal glutamate and ERG. We found that VEGF and BK stimulate glutamate release by astrocytes, however the BK effect occurs at an earlier time point than VEGF. The glutamate concentration per total retinal protein was elevated in retina treated with VEGF (1.38±0.07;; n=4) and BK (1.51±0.20;; n=3) compared to BSS (1.14±0.06;; n=4). Glutamate NMDA receptor inhibition did not block the BK effect on ERG as rats treated with MK801 still showed a BK induced increase in B-wave amplitude (330.35±23.71µV;; n=4) compared to BSS (270.48±4.02µV;; n=5). In rats treated with the NOS inhibitor, injection of VEGF resulted in an increase in retinal glutamate per total retinal protein (1.42±0.08;; n=4) as compared to BSS injection (1.04± 0.11;; n=4), suggesting that nitric oxide does not mediate glutamate release. However, NOS inhibition blocked the VEGF induced ERG B-wave amplitude increase (324.97±37.40µV;; n=4) as compared to the VEGF response in control rats (428.65±11.95µV;; n=4), indicating that NO mediates the ERG amplitude increase caused by VEGF. This data suggests that there are other neuro-active pathways besides glutamate that activate nNOS and amplify neuronal activity during retinal edema.
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