Retinal ischemic injury is common in patients with diabetes,
atherosclerosis,
hypertension, transient
ischemia attack and
amaurosis fugax. Previously, signs of ischemic stress, such as pericyte loss, blood-retinal barrier breakdown and neovascularization, which can lead to occlusion of retinal vessels, have been prevented in diabetic db/db mice with
aldose reductase (AR) null mutation. To determine the role in
retinal ischemic injury of AR and
sorbitol dehydrogenase (SDH), the first and second
enzymes in the
polyol pathway, mice with deletion of AR (AR(-/-)) or SDH-mutation (SDH(-/-)), or C57BL/6N mice treated with AR or SDH inhibitors were subjected to transient
retinal artery occlusion (2h of occlusion and 22h of reperfusion) by the intraluminal
suture method. Neuronal loss and
edema observed in wildtype (AR(+/+)) retinas after transient
ischemia were prevented in the retinas of AR(-/-) mice or C57BL/6N mice treated with an AR inhibitor,
Fidarestat. Fewer TUNEL-positive cells and smaller accumulations of
nitrotyrosine and
poly(ADP-ribose) were also observed in the retinas of AR(-/-) mice. However, SDH(-/-) mice and C57BL/6N mice treated with SDH inhibitor,
CP-470,711, were not protected against
ischemia-induced
retinal damage. Taken together, AR contributes to
retinal ischemic injury through increased
edema and
free radical accumulation. Therefore, AR inhibition should be considered for the treatment of
retinal ischemic injury often observed in diabetic patients.