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J. M. Petrash, A. Varma, T. M. Harter, P. A. Ruzycki, G. J. Zablocki, B. G. Reddy, S. Palla; Lens Phenotypes Associated With Transgenic Expression of Human Aldo-Keto Reductases. Invest. Ophthalmol. Vis. Sci. 2010;51(13):4595.
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To develop an animal model for testing and validating inhibitors of diabetic eye disease, we produced lines of transgenic mice that over-express either human aldose reductase (HAR, AKR1B1) or human small intestine reductase (HSIR, AKR1B10).
Lens transparency in transgenic lines that express roughly equivalent levels of either HAR/AKR1B1 or HSIR/AKR1B10 was monitored by slit lamp ophthalmoscopy for at least 6 weeks following induction of experimental diabetes (streptozocin). Digital images were examined by masked reviewers to score for the presence and extent of lens opacities. Effects of hyperglycemia were evaluated following organ culture of lenses in the presence of high glucose with or without an aldose reductase inhibitor. Sorbitol and glutathione levels were measured enzymatically.
Presence and severity of cataract was significantly higher in HAR/AKR1B1 transgenic as compared with nontransgenic control mice after induction of experimental diabetes. Virtually no difference in lens transparency was observed between HSIR/AKR1B10 transgenic and nontransgenic controls with or without diabetes induction. However, an anterior lens defect was observed in HSIR/AKR1B10 after long term (6 months) of diabetes. When organ cultured in the presence of high glucose (27.5 mM), lenses from HAR/AKR1B1 accumulated large amounts of sorbitol and lost approximately half of normal glutathione levels after 3 days; these changes were completely prevented by sorbinil. In contrast, lenses from HSIR/AKR1B10 and AR null mice failed to accumulate sorbitol and maintained normal levels of glutathione.
Aldose reductase is primarily responsible for diabetes-related sorbitol accumulation and oxidative stress associated with cataract formation in our mouse model. HSIR/AKR1B10 has little impact on lens metabolism and transparency even following diabetes induction.
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