Aldose reductase-deficient mice with diabetes are protected from the motor nerve conduction velocity deficit and axonal atrophy

Abstract

Recently, diabetes was recognized as an epidemic and considered as one of the major threats to human health in the 21st century due to hyperglycemia-associated complications. Hyperglycemia is thought to be responsible for microvascular changes causing hypoxia/ischemia and edema in retina leading to blindness and in peripheral nerve leading to debilitating neuropathies. It also affects the macrovascular vessels to brain and heart leading to higher risk of stroke. Hyperglycemia can also directly affect the metabolism of endothelial and neuronal cells causing reduced production of trophic and growth factors. Although it is clear that hyperglycemia-induced pathologies are multifactoral but how these diverse factors contribute to tissue damage is not clear. At present, there are five major hypotheses for the mechanism of hyperglycemia-associated tissue damage, including the activation of polyol pathway flux, PKC activation, increased advanced glycation end-product (AGE) formation and increased hexosamine pathway flux. Here, the role of polyol pathway in the etiology of pathogenesis of diabetic neuropathy using the genetic approach will be mainly discussed. This pathway consists of two enzymes, aldose reductase (AR), which converts glucose to sorbitol and sorbitol dehydrogenase (SD), which oxidize sorbitol to fructose. Under hyperglycemic condition, the exaggerated flux through AR leading to accumulation of sorbitol and osmotic stress is thought to be the major cause of tissue damage. By making use of transgenic mice with over-expression of human AR in Schwann cells only, we showed that the exaggerated flux through AR led to further reduction of motor nerve conduction velocity (MNCV) deficit but was not correlated with the level of sorbitol which is a minor osmolite in the sciatic nerve. This finding was confirmed also by the use of SD-deficient mice, which showed 17-fold more accumulation of sorbitol than the wildtype mice but did not show further reduction in the MNCV. In support of the proposal that consumption of NADPH by AR may affect other enzymes, which require NADPH, such as glutathione reductase, the sciatic nerve of diabetic AR transgenic mice showed the decreased level of reduced glutathoine (GSH). Other has shown that treatment with AR inhibitors (ARIs) can prevent sorbitol accumulation, GSH depletion, and improve MNCV deficits. However, the efficacy and specificity of ARIs in vivo have been questioned. To further clarify the role of AR as a major contributing factor to the pathogenesis of diabetic neuropathy, we generated the AR-deficient mice and determined the effect of AR-deficiency on the functional and biochemical changes in the nerve associated with diabetes. The supporting data to suggest that diabetic AR-deficient mice are protected from GSH depletion, MNCV deficit and axonal atrophy seen in the diabetic wildtype mice will be discussed.