The Effect of RAGE-Diaph1 Signaling Inhibition on the Progression of Peripheral Neuropathy in Diabetic Mice

Diabetic peripheral neuropathy (DPN) is a serious consequence of prolonged hyperglycemia and contributes to the morbidity associated with diabetes. Hyperglycemia enhances the non-enzymic glycation of proteins and the accumulation of Advanced Glycation End Products (AGEs). We employed a diabetic mouse model lacking both Diaph1 and RAGE to elucidate the role of RAGE-Diaph1 signaling in the pathogenesis of DPN. We demonstrate that simultaneous deletion of Diaph1 and RAGE did not change the course or the intensity of hyperglycemia-induced weight loss in mice. However, abrogating RAGE-Diaph1 signaling affects actin cytoskeleton remodeling rates in nerve axons by altering the ratio of the actin-regulating molecules cofilin and profilin. Our experimental results suggest that the loss of RAGE-Diaph1 signaling protects neurons from hyperglycemic conditions. We observed a beneficial effect of abolishing RAGE-Diaph1 signaling on the axonal structure of neuropathic nerves. In addition, we observed that abolishing RAGE-Diaph1 signaling improved motor nerve conduction velocity in the sciatic nerves of hyperglycemic mice. Our data indicate that RAGE-Diaph1 signaling is likely enhanced in chronic hyperglycemia, resulting in aberrant actin dynamics in nerve axons. These defective actin dynamics play a key role in the progression of DPN, leading to structural and functional loss in peripheral nerves.