Fundamental studies on the pathogenesis of diabetic complications using transgenic mice expressing human aldose reductase

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We have established transgenic mice, which express large amount of human aldose reductase, to explore the role of an enhanced polyol-pathway in the pathogenesis of diabetic complications. In our preceding studies, these transgenic mice exhibited significant accumulation of polyols by galactose feeding for 16 weeks associated with significant delay of motor nerve conduction velocity and nerve fiber atrophy of the peripheral nerve, thus demonstrating the implication of polyol pathway in the etiology of diabetic neuropathy. In the current study, we made transgenic mice diabetic for 8 weeks by intraperitoneal injection of streptozotocin and examined biochemical, electrophysiological and structural abnormalities in the peripheral nerve as well as renal lesions. Comparison was made with the changes in non-transgenic littermate control mice. Both transgenic and littermate control mice showed comparable levels of reduced body weight and hyperglycemia. By contrast, motor nerve conduction was mo … More st severely slowed in diabetic trasgenic mice followed by diabetic littermate mice compared to non-diabetic transgenic and littermate control mice. Biochemical measurements disclosed marked accumulation of sorbitol and fructose in diabetic transgenic mice, but such sugar levels were only modestly elevated in diabetic littermate mice. Myo-inositol levels were not altered in both diabetic groups. Morphometric analysis demonstrated significant myelinated fiber atrophy in diabetic transgenic mice compared with diabetic littermate and non-diabetic groups. These findings confirmed that transgenic mice for human aldose reductase developed severe neuropathic changes compared with diabetic littermate mice even under similar levels of hyperglycemia, suggesting that the aldose reductase expression is a critical determinant for the development of neuropathy and its severity. On the other hand, glomerular hypertrophy and mesangial expansion are characteristic changes of early renal lesions in human and animal diabetic nephropathy. Morphometric analysis on the kidney demonstrated significant enlargement of glomerular size and mesangial area in diabetic transgenic and littermate control mice as compared with ion-diabetic groups, while the values of diabetic transgenic mice were the greatest. These findings again indicate that an enhanced polyol pathway influences the development of diabetic glomerulopathy and an expression of aldose reductase mediates such an enhaneced activity of polyol pathway. Preliminary trials with aldose reductase inhibitors significantly inhibited neuropathic and glomerular changes in diabetic transgenic mice but not in diabetic littermate mace. It was thus concluded that the polyol pathway regulated by aldose reductase is an important determinant of the progression of diabetic complications and its effective inhibition may be valuable for the prevention and treatment of diabetic complications. Less