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Sergio Li Calzi, Lynn C. Shaw, Yuanqing Yan, Todd A. Lydic, Nan Li, Kristin Morris, Josef Neu, Julia V. Busik, Maria B. Grant; Arginine-glutamine (arg-gln) Supplementation Reduces Retinal Neovascularization (nv) And Stimulates Retinal Vessel Re-growth In A Mouse Model Of Retinopathy Of Prematurity (rop). Invest. Ophthalmol. Vis. Sci. 2011;52(14):3998.
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We have previously demonstrated diabetes-induced downregulation of retinal elongases with decreased retinal docosahexaenoic acid (DHA). Because of frequent insulin resistance in preterm infants, retinal changes may be recapitulated. Here, the effects of Arg-Gln on retinal fatty acid (FA) metabolism, vascular loss, regrowth after injury, and NV in a model of oxygen-induced retinopathy (OIR) were evaluated.
7-day old mouse pups were placed in 75% oxygen for five days then returned to room air on day 12 (P12) and gavaged twice daily with Arg-Gln (5 g/kg/d), DHA (2.5 g/kg/d), Arg-Gln + DHA, or vehicle through P17. when pups were sacrificed and perfused with FITC-dextran. Retinal NV was assessed by enumeration of pre-retinal endothelial cells and intra-retinal vascular density (VD). Retina DHA was measured by HPLC. Insulin receptor (IR) phosphorylation was assessed by western blot. Expression of the genes involved in FA metabolism was determined by RT-PCR.
Compared to vehicle, pre-retinal NV was reduced by 61% and 51% with Arg-Gln or DHA (p<0.05 both), with a 69% reduction observed for Arg-Gln + DHA (p<0.05). All treatments reduced vaso-obliteration vs. vehicle (32% vs. 5.2%, p<0.05). Arg-Gln, alone or with DHA, promoted intra-retinal VD vs. vehicle (73-76% vs. 53%). Feeding pups with Arg-Gln, as well as with DHA, normalized endogenous DHA levels in the OIR retinas (p<0.05 for all vs. contr.) through restoring IR phosphorylation and normalizing FA metabolic genes.
This is the first study demonstrating hyperoxia-induced changes in retinal FA metabolism. Arg-Gln decreased the avascular area of the retina by increasing vessel regrowth after injury, thereby reducing the hypoxic stimulus for NV. This protective effect of Arg-Gln was mediated, in part, through correcting insulin resistance via normalizing FA metabolism and levels of DHA. Normalization of retinal FA by Arg-Gln represents a potential therapy for ROP.
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