Establishment of mouse as an animal model for study of diabetic cataracts: biochemical studies.

Abstract

The primary aim of this study was to understand the pathogenesis of diabetic cataracts at biochemical level in an animal model where lens aldose reductase (AR) activity is low, similar to that in the human lens. Mouse, which is known to have low lens AR, was selected for these studies. Diabetes was induced by intraperitoneal administration of streptozotocin. Biochemical changes in the lens were monitored in freshly isolated lenses with standard chromatographic, enzymatic and culture experiments described in the section on methods. The present studies provide evidence of significant biochemical changes associated with such cataract formation despite very low levels of aldose reductase. The level of glycated proteins increased to 9 mg/100 mg of total water-soluble lens protein in the diabetic lenses, as compared with the normal lenses where it was only about 1.3 mg/100 mg of total protein. Glutathione (GSH), the major antioxidant in the lens, decreased from 2.35 micro mol/g in the normal lenses to about 1.17 micro mol/g in the diabetic lenses. Malonadehyde, a product of lipid peroxidation, increased from 50 micro mol/100 g in the normal to 70 micro mol/100 g in the diabetic lens. The level of adenosine triphosphate (ATP), an indicator of the overall metabolic status of the tissue, also decreased from 962 +/- 154 nmol/g in the normal to 487 +/- 130 nmol/g in the diabetic lenses. The function of the Na+-K+ ATPase was also adversely affected in diabetes, as indicated by the ability of the lens to accumulate (86)rubidium ions against its concentration gradient. The transport activity, expressed as CL/CM, was 24 in the normal lens, whereas it was only 12 in the diabetic lens. The level of sorbitol in the diabetic lens was only in the micromolar region. Hence, it was considered osmotically insignificant. Overall, the results suggest that induction of cataracts in diabetes can be related to multiple biochemical effects such as oxidative stress and glycation. Sorbitol accumulation in low aldose reductase situations, being minor, could, however, act synergistically with other factors.