The dipeptide Arg-Gln inhibits retinal neovascularization in the mouse model of oxygen-induced retinopathy

Josef Neu, Aqeela Afzal, Hao Pan, Esteban Gallego, Nan Li, Sergio Li Calzi, Sergio Caballero, Polyxenie E. Spoerri, Lynn C. Shaw, Maria B. Grant

Research output: Contribution to journalArticle

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Abstract

PURPOSE. Premature infants undergoing intensive care are highly vulnerable to amino acid deprivation. Supplementation of glutamine or arginine has resulted in beneficial effects in human neonates. This study was conducted to examine the effect of the dipeptide arginyl-glutamine (Arg-Gln) on vascular endothelial cell growth factor (VEGF) levels in primary human retinal pigment epithelial (hRPE) cell cultures and on inhibition of neovascularization in the oxygen-induced retinopathy (OIR) model. METHODS. The effects of Arg-Gln on VEGF levels were measured in supernates from hRPE cells by using ELISAs. For in vivo studies, mouse pups received twice-daily intraperitoneal injections of Arg-Gln, a control dipeptide (Ala-Gly) or were not injected. Retinal flatmounts from one cohort were prepared and retinal vessel morphology examined. The contralateral eyes were embedded, sectioned, and stained to count preretinal neovascular nuclei. RNA was isolated from retinas of selected animals and was used to quantify VEGF mRNA by real-time RT-PCR. RESULTS. Treatment of hRPE cells with Arg-Gln decreased VEGF levels in a dose-dependent manner. In the OIR model, Arg-Gln at 5 g/kg per day reduced preretinal neovascularization by 82% ± 7% (P <0.005), when compared with the control dipeptide Ala-Gly, and reduced VEGF mRNA by 64% ± 9% (P <0.001). CONCLUSIONS. Arg-Gln dramatically inhibited retinal neovascularization in the OIR model. This effect was associated with a reduction in retinal VEGF mRNA levels. Similarly the dipeptide reduced VEGF expression in hRPE cells, a cell type likely to respond to retinal hypoxia by expressing VEGF. Arg-Gln appears to be safe and, with future studies in human infants, may prove beneficial in the prevention of ROP.

Original languageEnglish (US)
Pages (from-to)3151-3155
Number of pages5
JournalInvestigative Ophthalmology and Visual Science
Volume47
Issue number7
DOIs
StatePublished - Jul 2006
Externally publishedYes

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arginyl-glutamine
Retinal Neovascularization
Dipeptides
Vascular Endothelial Growth Factor A
Oxygen
Retinal Pigments
alanylglycine
Epithelial Cells
Messenger RNA
Retinal Vessels
Critical Care
Intraperitoneal Injections
Glutamine
Premature Infants
Arginine
Retina
Real-Time Polymerase Chain Reaction

ASJC Scopus subject areas

  • Ophthalmology

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The dipeptide Arg-Gln inhibits retinal neovascularization in the mouse model of oxygen-induced retinopathy. / Neu, Josef; Afzal, Aqeela; Pan, Hao; Gallego, Esteban; Li, Nan; Li Calzi, Sergio; Caballero, Sergio; Spoerri, Polyxenie E.; Shaw, Lynn C.; Grant, Maria B.

In: Investigative Ophthalmology and Visual Science, Vol. 47, No. 7, 07.2006, p. 3151-3155.

Research output: Contribution to journalArticle

Neu, J, Afzal, A, Pan, H, Gallego, E, Li, N, Li Calzi, S, Caballero, S, Spoerri, PE, Shaw, LC & Grant, MB 2006, 'The dipeptide Arg-Gln inhibits retinal neovascularization in the mouse model of oxygen-induced retinopathy', Investigative Ophthalmology and Visual Science, vol. 47, no. 7, pp. 3151-3155. https://doi.org/10.1167/iovs.05-1473
Neu, Josef ; Afzal, Aqeela ; Pan, Hao ; Gallego, Esteban ; Li, Nan ; Li Calzi, Sergio ; Caballero, Sergio ; Spoerri, Polyxenie E. ; Shaw, Lynn C. ; Grant, Maria B. / The dipeptide Arg-Gln inhibits retinal neovascularization in the mouse model of oxygen-induced retinopathy. In: Investigative Ophthalmology and Visual Science. 2006 ; Vol. 47, No. 7. pp. 3151-3155.
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abstract = "PURPOSE. Premature infants undergoing intensive care are highly vulnerable to amino acid deprivation. Supplementation of glutamine or arginine has resulted in beneficial effects in human neonates. This study was conducted to examine the effect of the dipeptide arginyl-glutamine (Arg-Gln) on vascular endothelial cell growth factor (VEGF) levels in primary human retinal pigment epithelial (hRPE) cell cultures and on inhibition of neovascularization in the oxygen-induced retinopathy (OIR) model. METHODS. The effects of Arg-Gln on VEGF levels were measured in supernates from hRPE cells by using ELISAs. For in vivo studies, mouse pups received twice-daily intraperitoneal injections of Arg-Gln, a control dipeptide (Ala-Gly) or were not injected. Retinal flatmounts from one cohort were prepared and retinal vessel morphology examined. The contralateral eyes were embedded, sectioned, and stained to count preretinal neovascular nuclei. RNA was isolated from retinas of selected animals and was used to quantify VEGF mRNA by real-time RT-PCR. RESULTS. Treatment of hRPE cells with Arg-Gln decreased VEGF levels in a dose-dependent manner. In the OIR model, Arg-Gln at 5 g/kg per day reduced preretinal neovascularization by 82{\%} ± 7{\%} (P <0.005), when compared with the control dipeptide Ala-Gly, and reduced VEGF mRNA by 64{\%} ± 9{\%} (P <0.001). CONCLUSIONS. Arg-Gln dramatically inhibited retinal neovascularization in the OIR model. This effect was associated with a reduction in retinal VEGF mRNA levels. Similarly the dipeptide reduced VEGF expression in hRPE cells, a cell type likely to respond to retinal hypoxia by expressing VEGF. Arg-Gln appears to be safe and, with future studies in human infants, may prove beneficial in the prevention of ROP.",
author = "Josef Neu and Aqeela Afzal and Hao Pan and Esteban Gallego and Nan Li and {Li Calzi}, Sergio and Sergio Caballero and Spoerri, {Polyxenie E.} and Shaw, {Lynn C.} and Grant, {Maria B.}",
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T1 - The dipeptide Arg-Gln inhibits retinal neovascularization in the mouse model of oxygen-induced retinopathy

AU - Neu, Josef

AU - Afzal, Aqeela

AU - Pan, Hao

AU - Gallego, Esteban

AU - Li, Nan

AU - Li Calzi, Sergio

AU - Caballero, Sergio

AU - Spoerri, Polyxenie E.

AU - Shaw, Lynn C.

AU - Grant, Maria B.

PY - 2006/7

Y1 - 2006/7

N2 - PURPOSE. Premature infants undergoing intensive care are highly vulnerable to amino acid deprivation. Supplementation of glutamine or arginine has resulted in beneficial effects in human neonates. This study was conducted to examine the effect of the dipeptide arginyl-glutamine (Arg-Gln) on vascular endothelial cell growth factor (VEGF) levels in primary human retinal pigment epithelial (hRPE) cell cultures and on inhibition of neovascularization in the oxygen-induced retinopathy (OIR) model. METHODS. The effects of Arg-Gln on VEGF levels were measured in supernates from hRPE cells by using ELISAs. For in vivo studies, mouse pups received twice-daily intraperitoneal injections of Arg-Gln, a control dipeptide (Ala-Gly) or were not injected. Retinal flatmounts from one cohort were prepared and retinal vessel morphology examined. The contralateral eyes were embedded, sectioned, and stained to count preretinal neovascular nuclei. RNA was isolated from retinas of selected animals and was used to quantify VEGF mRNA by real-time RT-PCR. RESULTS. Treatment of hRPE cells with Arg-Gln decreased VEGF levels in a dose-dependent manner. In the OIR model, Arg-Gln at 5 g/kg per day reduced preretinal neovascularization by 82% ± 7% (P <0.005), when compared with the control dipeptide Ala-Gly, and reduced VEGF mRNA by 64% ± 9% (P <0.001). CONCLUSIONS. Arg-Gln dramatically inhibited retinal neovascularization in the OIR model. This effect was associated with a reduction in retinal VEGF mRNA levels. Similarly the dipeptide reduced VEGF expression in hRPE cells, a cell type likely to respond to retinal hypoxia by expressing VEGF. Arg-Gln appears to be safe and, with future studies in human infants, may prove beneficial in the prevention of ROP.

AB - PURPOSE. Premature infants undergoing intensive care are highly vulnerable to amino acid deprivation. Supplementation of glutamine or arginine has resulted in beneficial effects in human neonates. This study was conducted to examine the effect of the dipeptide arginyl-glutamine (Arg-Gln) on vascular endothelial cell growth factor (VEGF) levels in primary human retinal pigment epithelial (hRPE) cell cultures and on inhibition of neovascularization in the oxygen-induced retinopathy (OIR) model. METHODS. The effects of Arg-Gln on VEGF levels were measured in supernates from hRPE cells by using ELISAs. For in vivo studies, mouse pups received twice-daily intraperitoneal injections of Arg-Gln, a control dipeptide (Ala-Gly) or were not injected. Retinal flatmounts from one cohort were prepared and retinal vessel morphology examined. The contralateral eyes were embedded, sectioned, and stained to count preretinal neovascular nuclei. RNA was isolated from retinas of selected animals and was used to quantify VEGF mRNA by real-time RT-PCR. RESULTS. Treatment of hRPE cells with Arg-Gln decreased VEGF levels in a dose-dependent manner. In the OIR model, Arg-Gln at 5 g/kg per day reduced preretinal neovascularization by 82% ± 7% (P <0.005), when compared with the control dipeptide Ala-Gly, and reduced VEGF mRNA by 64% ± 9% (P <0.001). CONCLUSIONS. Arg-Gln dramatically inhibited retinal neovascularization in the OIR model. This effect was associated with a reduction in retinal VEGF mRNA levels. Similarly the dipeptide reduced VEGF expression in hRPE cells, a cell type likely to respond to retinal hypoxia by expressing VEGF. Arg-Gln appears to be safe and, with future studies in human infants, may prove beneficial in the prevention of ROP.

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