The RAGE axis in early diabetic retinopathy.
OBJECTIVE
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.
Barile
Gaetano R
GR
Department of Ophthalmology, Mailman School of Public Health, Columbia University, New York, NY, USA. grb17@columbia.edu
Pachydaki
Sophia I
SI
Tari
Samir R
SR
Lee
Song E
SE
Donmoyer
Christine M
CM
Ma
Wanchao
W
Rong
Ling Ling
LL
Buciarelli
Loredana G
LG
Wendt
Thoralf
T
Hörig
Heidi
H
Hudson
Barry I
BI
Qu
Wu
W
Weinberg
Alan D
AD
Yan
Shi Fang
SF
Schmidt
Ann Marie
AM
D000818:Animals; D001057:Apolipoproteins E / Q000378:metabolism*; D003930:Diabetic Retinopathy / Q000378:metabolism* / Q000503:physiopathology; D004596:Electroretinography; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005453:Fluorescence; D019084:Fluorescent Antibody Technique, Indirect; D015870:Gene Expression; D017127:Glycation End Products, Advanced / Q000235:genetics / Q000378:metabolism*; D006943:Hyperglycemia / Q000378:metabolism* / Q000473:pathology; D006949:Hyperlipidemias / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D012171:Retinal Vessels / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction
D001057:Apolipoproteins E; D017127:Glycation End Products, Advanced; D012333:RNA, Messenger; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic