Synergistic effect of osmotic and oxidative stress in slow-developing cataract formation

Diabetes is a major contributing factor in cataract development. In animal models where cataracts develop within days or weeks of diabetes it is well established that osmotic stress from the accumulation of sorbitol leads to cataract development. This mechanism might explain the rare cases of acute cataract sometimes found in patients with uncontrolled sustained hyperglycemia but cannot account for the vast majority of cataracts that developed after years of diabetes. Thus, a model that can simulate diabetic slow-developing cataract is needed. The contribution of osmotic and oxidative stress in cataract development in sorbitol dehydrogenase (SDH) deficient mice, a model for slow-developing cataract in diabetic patients was determined. Contribution of osmotic stress was assessed by HPLC measurement of sorbitol and by observing the effect of blocking sorbitol accumulation by aldose reductase (AR) null mutation in the SDH deficient mice. Contribution of oxidative stress was assessed by observing the effect of vitamin E treatment and the effect of null mutation of glutathione peroxidase-1 (Gpx-1) on cataract development in these mice. Lenticular sorbitol level was significantly increased in the SDH deficient mice, and blocking sorbitol accumulation by the AR null mutation prevented cataract development, demonstrating the contribution of osmotic stress in cataract development. SDH deficiency did not affect lens oxidative stress status. However, treatment with vitamin E significantly reduced the incidence of cataract, and Gpx-1 deficiency exacerbated cataract development in these mice. Our findings suggest that chronic oxidative stress impaired the osmoregulatory mechanism of the lens. This was not evident until modest increases in lens sorbitol increased the demand of its osmoregulatory function. This osmoregulatory dysfunction model is supported by the fact that the activity of Na+/K+-ATPase, the key regulator of cellular ions and water balance, was dramatically reduced in the precataractous lenses of the SDH deficient mice, and that treatment with vitamin E prevented the loss of Na+/K+-ATPase activity. This osmoregulatory dysfunction model might explain why diabetic patients who control their blood glucose moderately well are still susceptible to develop cataract.