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Diabetes 54:3119-3125, 2005
© 2005 by the American Diabetes Association, Inc.

Aldose Reductase Deficiency Prevents Diabetes-Induced Blood-Retinal Barrier Breakdown, Apoptosis, and Glial Reactivation in the Retina of db/db Mice

Alvin K.H. Cheung1,2, Maggie K.L. Fung1,2, Amy C.Y. Lo1,2, Terence T.L. Lam1, Kwok Fai So2, Stephen S.M. Chung1,3, and Sookja K. Chung1,2

1 Institute of Molecular Biology, The University of Hong Kong, Hong Kong, China
2 Department of Anatomy, The University of Hong Kong, Hong Kong, China
3 Department of Physiology, The University of Hong Kong, Hong Kong, China

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.

Address correspondence and reprint requests to Dr. Sookja K. Chung, Department of Anatomy, 1/F, Laboratory Block, Faculty of Medicine Building, 21 Sassoon Rd., The University of Hong Kong, Hong Kong, China. E-mail: skchung{at}hkucc.hku.hk

Abbreviations: AR, aldose reductase; GFAP, glial fibrillary acidic protein; PAR, poly(ADP-ribose); PARP, PAR polymerase; PCNA, proliferating cell nuclear antigen; PECAM-1, platelet/endothelial cell adhesion molecule-1; SMA, smooth muscle actin; VEGF, vascular endothelial growth factor


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Diabetes Diabetes Care Clinical Diabetes Diabetes Spectrum
Copyright © 2005 by the American Diabetes Association.