The RAGE axis in early diabetic retinopathy

Gaetano R. Barile, Sophia I. Pachydaki, Samir R. Tari, Song E. Lee, Christine M. Donmoyer, Wanchao Ma, Ling Ling Rong, Loredana G. Buciarelli, Thoralf Wendt, Heidi Hörig, Barry Hudson, Wu Qu, Alan D. Weinberg, Shi Fang Yan, Ann Marie Schmidt

Research output: Contribution to journalArticle

164 Citations (Scopus)

Abstract

PURPOSE. The receptor for advanced glycation end products (AGEs) has been implicated in the pathogenesis of diabetic complications. This study was conducted to characterize the role of the RAGE axis in a murine model of nonproliferative diabetic retinopathy (NPDR). METHODS. The retinas of hyperglycemic, hyperlipidemic (HGHL, apolipoprotein E-/- db/db) mice were examined for the development of early retinal vascular lesions of NPDR and compared to littermates at 6 months of age. Neural function was assessed with electroretinography. Immunohistochemistry, real-time RT-PCR, autofluorescence, and ELISA studies were used to localize and quantify the AGE/RAGE axis. Soluble RAGE, a competitor of cellular RAGE for its ligands, was administered to assess the impact of RAGE blockade. RESULTS. Early inner retinal neuronal dysfunction, manifested by prolonged latencies of the oscillatory potentials and b-wave, was detected in hyperglycemic mice. HGHL mice exhibited accelerated development of acellular capillaries and pericyte ghosts compared with littermate control animals. AGEs were localized primarily to the vitreous cavity and internal limiting membrane (ILM) of the retina, where they were intimately associated with the footplates of RAGE-expressing Müller cells. AGE accumulation measured by ELISA was increased within the retinal extracellular matrix of hyperglycemic mice. AGE fluorescence and upregulation of RAGE transcripts was highest in the retinas of HGHL mice, and attenuation of the RAGE axis with soluble RAGE ameliorated neuronal dysfunction and reduced the development of capillary lesions in these mice. CONCLUSIONS. In early diabetic retinopathy, the RAGE axis, comprising the cellular receptor and its AGE ligands, is amplified within the retina and is accentuated along the vitreoretinal interface. Antagonism of the RAGE axis in NPDR reduces neurovascular perturbations, providing an important therapeutic target for intervention.

Original languageEnglish
Pages (from-to)2916-2924
Number of pages9
JournalInvestigative Ophthalmology and Visual Science
Volume46
Issue number8
DOIs
StatePublished - Dec 1 2005
Externally publishedYes

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Diabetic Retinopathy
Retina
Obese Mice
Enzyme-Linked Immunosorbent Assay
Ligands
Electroretinography
Retinal Vessels
Pericytes
Apolipoproteins E
Diabetes Complications
Extracellular Matrix
Real-Time Polymerase Chain Reaction
Up-Regulation
Fluorescence
Immunohistochemistry
Membranes
Advanced Glycosylation End Product-Specific Receptor
Therapeutics

ASJC Scopus subject areas

  • Ophthalmology

Cite this

Barile, G. R., Pachydaki, S. I., Tari, S. R., Lee, S. E., Donmoyer, C. M., Ma, W., ... Schmidt, A. M. (2005). The RAGE axis in early diabetic retinopathy. Investigative Ophthalmology and Visual Science, 46(8), 2916-2924. https://doi.org/10.1167/iovs.04-1409

The RAGE axis in early diabetic retinopathy. / Barile, Gaetano R.; Pachydaki, Sophia I.; Tari, Samir R.; Lee, Song E.; Donmoyer, Christine M.; Ma, Wanchao; Rong, Ling Ling; Buciarelli, Loredana G.; Wendt, Thoralf; Hörig, Heidi; Hudson, Barry; Qu, Wu; Weinberg, Alan D.; Yan, Shi Fang; Schmidt, Ann Marie.

In: Investigative Ophthalmology and Visual Science, Vol. 46, No. 8, 01.12.2005, p. 2916-2924.

Research output: Contribution to journalArticle

Barile, GR, Pachydaki, SI, Tari, SR, Lee, SE, Donmoyer, CM, Ma, W, Rong, LL, Buciarelli, LG, Wendt, T, Hörig, H, Hudson, B, Qu, W, Weinberg, AD, Yan, SF & Schmidt, AM 2005, 'The RAGE axis in early diabetic retinopathy', Investigative Ophthalmology and Visual Science, vol. 46, no. 8, pp. 2916-2924. https://doi.org/10.1167/iovs.04-1409
Barile GR, Pachydaki SI, Tari SR, Lee SE, Donmoyer CM, Ma W et al. The RAGE axis in early diabetic retinopathy. Investigative Ophthalmology and Visual Science. 2005 Dec 1;46(8):2916-2924. https://doi.org/10.1167/iovs.04-1409
Barile, Gaetano R. ; Pachydaki, Sophia I. ; Tari, Samir R. ; Lee, Song E. ; Donmoyer, Christine M. ; Ma, Wanchao ; Rong, Ling Ling ; Buciarelli, Loredana G. ; Wendt, Thoralf ; Hörig, Heidi ; Hudson, Barry ; Qu, Wu ; Weinberg, Alan D. ; Yan, Shi Fang ; Schmidt, Ann Marie. / The RAGE axis in early diabetic retinopathy. In: Investigative Ophthalmology and Visual Science. 2005 ; Vol. 46, No. 8. pp. 2916-2924.
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AU - Barile, Gaetano R.

AU - Pachydaki, Sophia I.

AU - Tari, Samir R.

AU - Lee, Song E.

AU - Donmoyer, Christine M.

AU - Ma, Wanchao

AU - Rong, Ling Ling

AU - Buciarelli, Loredana G.

AU - Wendt, Thoralf

AU - Hörig, Heidi

AU - Hudson, Barry

AU - Qu, Wu

AU - Weinberg, Alan D.

AU - Yan, Shi Fang

AU - Schmidt, Ann Marie

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N2 - PURPOSE. The receptor for advanced glycation end products (AGEs) has been implicated in the pathogenesis of diabetic complications. This study was conducted to characterize the role of the RAGE axis in a murine model of nonproliferative diabetic retinopathy (NPDR). METHODS. The retinas of hyperglycemic, hyperlipidemic (HGHL, apolipoprotein E-/- db/db) mice were examined for the development of early retinal vascular lesions of NPDR and compared to littermates at 6 months of age. Neural function was assessed with electroretinography. Immunohistochemistry, real-time RT-PCR, autofluorescence, and ELISA studies were used to localize and quantify the AGE/RAGE axis. Soluble RAGE, a competitor of cellular RAGE for its ligands, was administered to assess the impact of RAGE blockade. RESULTS. Early inner retinal neuronal dysfunction, manifested by prolonged latencies of the oscillatory potentials and b-wave, was detected in hyperglycemic mice. HGHL mice exhibited accelerated development of acellular capillaries and pericyte ghosts compared with littermate control animals. AGEs were localized primarily to the vitreous cavity and internal limiting membrane (ILM) of the retina, where they were intimately associated with the footplates of RAGE-expressing Müller cells. AGE accumulation measured by ELISA was increased within the retinal extracellular matrix of hyperglycemic mice. AGE fluorescence and upregulation of RAGE transcripts was highest in the retinas of HGHL mice, and attenuation of the RAGE axis with soluble RAGE ameliorated neuronal dysfunction and reduced the development of capillary lesions in these mice. CONCLUSIONS. In early diabetic retinopathy, the RAGE axis, comprising the cellular receptor and its AGE ligands, is amplified within the retina and is accentuated along the vitreoretinal interface. Antagonism of the RAGE axis in NPDR reduces neurovascular perturbations, providing an important therapeutic target for intervention.

AB - PURPOSE. The receptor for advanced glycation end products (AGEs) has been implicated in the pathogenesis of diabetic complications. This study was conducted to characterize the role of the RAGE axis in a murine model of nonproliferative diabetic retinopathy (NPDR). METHODS. The retinas of hyperglycemic, hyperlipidemic (HGHL, apolipoprotein E-/- db/db) mice were examined for the development of early retinal vascular lesions of NPDR and compared to littermates at 6 months of age. Neural function was assessed with electroretinography. Immunohistochemistry, real-time RT-PCR, autofluorescence, and ELISA studies were used to localize and quantify the AGE/RAGE axis. Soluble RAGE, a competitor of cellular RAGE for its ligands, was administered to assess the impact of RAGE blockade. RESULTS. Early inner retinal neuronal dysfunction, manifested by prolonged latencies of the oscillatory potentials and b-wave, was detected in hyperglycemic mice. HGHL mice exhibited accelerated development of acellular capillaries and pericyte ghosts compared with littermate control animals. AGEs were localized primarily to the vitreous cavity and internal limiting membrane (ILM) of the retina, where they were intimately associated with the footplates of RAGE-expressing Müller cells. AGE accumulation measured by ELISA was increased within the retinal extracellular matrix of hyperglycemic mice. AGE fluorescence and upregulation of RAGE transcripts was highest in the retinas of HGHL mice, and attenuation of the RAGE axis with soluble RAGE ameliorated neuronal dysfunction and reduced the development of capillary lesions in these mice. CONCLUSIONS. In early diabetic retinopathy, the RAGE axis, comprising the cellular receptor and its AGE ligands, is amplified within the retina and is accentuated along the vitreoretinal interface. Antagonism of the RAGE axis in NPDR reduces neurovascular perturbations, providing an important therapeutic target for intervention.

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