Exploration of pathogenesis of diabetic complications using transgenic mice and attempts of gene therapy

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To explore the mechanisms of diabetic complications and to establish the direction for the prevention and treatment of them, we studied biochemical, physiological and pathological changes in microvessels and peripheral nerve tissues using recently developed transgenic animal models. In this study, we used transgenic mice overexpressing human aldose reductase (AR) and knockout mice that were deficient of AR to examine the role of polyol pathway. On the other hand, transgenic mice that overexpress receptor for advanced glycation endproducts (RAGE) were used to see the effects of RAGE overexpression in the endothelial cells on the development of diabetic complications. These mouse models were made diabetic by intravenous injection of streptozotocin and followed for 16 weeks. The diabetic AR mice exhibited marked depression of protein kinase C (PKC) activity in the nerve while PKC activity was contrariwise elevated in vascular tissues. These changes were due to reduced membrane expression … More of PKC-alpha in the nerve and increased membrane expression of PKC-beta in vascular tissues. These alterations were associated with significant functional and structural pathology in nerve and vessels in diabetic animals and not found in diabetic AR-knockout mice. Inhibitors for AR effectively prevented all the changes. Thus, it was concluded that AR plays a crucial role in the cause of diabetic complications and its inhibition is effective for the prevention and treatment. However, under very severe hyperglycemia, even AR knockout mice could not escape the pathological changes of diabetic complications and other mechanisms were thought to exert for tissue injury. As one possible mechanism, RAGE overexpression induced more severe tissue damage compared to control diabetic mice, thus suggesting the implication of AGE-RAGE interaction for the development of diabetic complications. The current series of studies clearly demonstrated the multiple factors implicating in the cause of diabetic complications and we consider that multi-facet directions for the prevention and treatment will be essential for the clinical applications. Less