P66SHC DEFICIENCY ATTENUATES HIGH GLUCOSE-INDUCED AUTOPHAGY DYSFUNCTION

Objective: This study aimed to explore the potential role of p66shc in mediating high glucose-induced oxidative stress and autophagic dysfunction in Schwann cells, the most abundant cell type in the peripheral nervous system. By examining the role of p66shc in Schwann cell injury responses, this study sought to provide insights into the pathogenesis of diabetic peripheral neuropathy (DPN). Design and method: Schwann cells treated with high glucose were analyzed for p66shc expression, reactive oxygen species (ROS) levels, autophagic impairment, and early apoptosis. p66shc gene expression was inhibited using siRNA to investigate its role in reversing the effects of high glucose exposure. In streptozotocin (STZ)-induced diabetic mice, the expression of p66shc and autophagy-related proteins (p62 and LC3-II/I) in the sciatic nerve were examined. The improvement of autophagy dysfunction was evaluated in p66shc-deficient mice after the onset of diabetes. Results: High glucose treatment increased p66shc expression, elevated ROS production, impaired autophagy, and induced early apoptosis in Schwann cells. Inhibition of p66shc expression by siRNA attenuated high glucose-induced oxidative stress, autophagic dysfunction, and early apoptosis. Diabetic mice exhibited increased p66shc expression and suppressed levels of autophagy-related proteins (p62 and LC3-II/I) in the sciatic nerve. p66shc-deficient mice showed improvements in autophagic dysfunction after the onset of diabetes. Conclusions: p66shc plays a crucial role in high glucose-induced Schwann cell dysfunction, primarily by promoting oxidative stress and impairing autophagy. Deficiency of p66shc alleviates these pathological changes, highlighting its potential as a therapeutic target for diabetic peripheral neuropathy.