Aldose reductase deficiency prevents diabetes-induced blood-retinal barrier breakdown, apoptosis, and glial reactivation in the retina of db/db mice.
In 15-month-old db/db mice, signs of diabetic retinopathy, including blood-retinal barrier breakdown, loss of pericytes, neuro-retinal apoptosis, glial reactivation, and proliferation of blood vessels, were evident. These changes in the diabetic retina were associated with increased expression of aldose reductase (AR). To further understand the role of AR in the pathogenesis of diabetic retinopathy, we generated db/db mice with an AR null mutation (AR-/- db/db). AR deficiency led to fewer retinal blood vessels with IgG leakage, suggesting that AR may contribute to blood-retinal barrier breakdown. AR deficiency also prevented diabetes-induced reduction of platelet/endothelial cell adhesion molecule-1 expression and increased expression of vascular endothelial growth factor, which may have contributed to blood-retinal barrier breakdown. In addition, long-term diabetes-induced neuro-retinal stress and apoptosis and proliferation of blood vessels were less prominent in AR-/- db/db mice. These findings indicate that AR is responsible for the early events in the pathogenesis of diabetic retinopathy, leading to a cascade of retinal lesions, including blood-retinal barrier breakdown, loss of pericytes, neuro-retinal apoptosis, glial reactivation, and neovascularization.
Cheung
Alvin K H
AK
Institute of Molecular Biology, The University of Hong Kong, Hong Kong, China.
Fung
Maggie K L
MK
Lo
Amy C Y
AC
Lam
Terence T L
TT
So
Kwok Fai
KF
Chung
Stephen S M
SS
Chung
Sookja K
SK
D000449:Aldehyde Reductase / Q000172:deficiency* / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001813:Blood-Retinal Barrier / Q000503:physiopathology*; D049109:Cell Proliferation; D003920:Diabetes Mellitus / Q000235:genetics / Q000503:physiopathology*; D017353:Gene Deletion; D015971:Gene Expression Regulation, Enzymologic; D051379:Mice; D009457:Neuroglia; D018384:Oxidative Stress; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000235:genetics; D012160:Retina / Q000166:cytology* / Q000201:enzymology*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
D019408:Platelet Endothelial Cell Adhesion Molecule-1; D042461:Vascular Endothelial Growth Factor A; D000449:Aldehyde Reductase