Müller glial dysfunction during diabetic retinopathy in rats is linked to accumulation of advanced glycation end-products and advanced lipoxidation end-products.
OBJECTIVE
The impact of AGEs and advanced lipoxidation end-products (ALEs) on neuronal and Müller glial dysfunction in the diabetic retina is not well understood. We therefore sought to identify dysfunction of the retinal Müller glia during diabetes and to determine whether inhibition of AGEs/ALEs can prevent it.


METHODS
Sprague-Dawley rats were divided into three groups: (1) non-diabetic; (2) untreated streptozotocin-induced diabetic; and (3) diabetic treated with the AGE/ALE inhibitor pyridoxamine for the duration of diabetes. Rats were killed and their retinas were evaluated for neuroglial pathology.


RESULTS
AGEs and ALEs accumulated at higher levels in diabetic retinas than in controls (p < 0.001). AGE/ALE immunoreactivity was significantly diminished by pyridoxamine treatment of diabetic rats. Diabetes was also associated with the up-regulation of the oxidative stress marker haemoxygenase-1 and the induction of glial fibrillary acidic protein production in Müller glia (p < 0.001). Pyridoxamine treatment of diabetic rats had a significant beneficial effect on both variables (p < 0.001). Diabetes also significantly altered the normal localisation of the potassium inwardly rectifying channel Kir4.1 and the water channel aquaporin 4 to the Müller glia end-feet interacting with retinal capillaries. These abnormalities were prevented by pyridoxamine treatment.


CONCLUSIONS
While it is established that AGE/ALE formation in the retina during diabetes is linked to microvascular dysfunction, this study suggests that these pathogenic adducts also play a role in Müller glial dysfunction.
Centre for Vision and Vascular Science, Queen's University Belfast, Royal Victoria Hospital, Belfast BT12 6BA, Northern Ireland, UK.
T M
TM
Curtis
R
R
Hamilton
P-H
PH
Yong
C M
CM
McVicar
A
A
Berner
R
R
Pringle
K
K
Uchida
R
R
Nagai
S
S
Brockbank
A W
AW
Stitt
D000818:Animals; D003930:Diabetic Retinopathy / Q000378:metabolism* / Q000473:pathology*; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D015227:Lipid Peroxidation / Q000502:physiology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012160:Retina / Q000378:metabolism / Q000473:pathology*; D012165:Retinal Ganglion Cells / Q000378:metabolism* / Q000473:pathology*; D055351:Retinal Neurons / Q000378:metabolism / Q000473:pathology
D017127:Glycation End Products, Advanced