Gene deletion and pharmacological inhibition of aldose reductase protect against retinal ischemic injury.
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.
Cheung
Alvin K H
AK
Department of Anatomy, The University of Hong Kong, Pokfulam Road, Hong Kong, China.
Lo
Amy C Y
AC
So
Kwok Fai
KF
Chung
Stephen S M
SS
Chung
Sookja K
SK
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D017353:Gene Deletion; D018698:Glutamic Acid / Q000378:metabolism; D048289:Imidazolidines / Q000627:therapeutic use; D007064:L-Iditol 2-Dehydrogenase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009457:Neuroglia / Q000378:metabolism; D018384:Oxidative Stress; D010211:Papilledema / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control; D011743:Pyrimidines / Q000627:therapeutic use; D015427:Reperfusion Injury / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D012164:Retinal Diseases / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D012165:Retinal Ganglion Cells / Q000473:pathology
C467608:CP-470711; D048289:Imidazolidines; D011743:Pyrimidines; D018698:Glutamic Acid; C077139:fidarestat; D007064:L-Iditol 2-Dehydrogenase; D000449:Aldehyde Reductase