Overexpression of Membrane Metalloendopeptidase Attenuates Oxidative Stress and Inflammation in Diabetic Neuropathy via the Nrf2/HO-1 Pathway

Objective: To investigate the role of Membrane Metalloendopeptidase (MME) in oxidative stress and inflammation in painful diabetic neuropathy, and to explore the underlying mechanism. Methods: A diabetic mouse model was established with streptozocin (STZ) injections. Neuropathic pain was assessed using paw withdrawal latency (PWL). Target genes related to painful diabetic neuropathy were identified using the Comparative Toxicogenomic Database (CTD), DisGeNET, and GeneCards. Protein-protein interactions between MME and the Nrf2/HO-1 signaling pathway were analyzed using the String database. The effects of MME overexpression, with or without the Nrf2 inhibitor ML385, on neuropathy were examined. Blood glucose, insulin levels, oxidative stress indicators, and inflammatory cytokines were measured. Gene expression was quantified by qRT-PCR, and protein levels were assessed by Western blot and immunohistochemistry. Results: Diabetic mice showed elevated blood glucose, MDA, ROS, TNF-α, IL-1β, IL-6, and decreased serum insulin, PWL, SOD activity, and MME levels. MME interacted with Nrf2 and HO-1, which were reduced in diabetic mice. Overexpression of MME led to improved serum insulin, PWL, SOD activity, and increased Nrf2 and HO-1 levels, while reducing MDA, ROS, TNF-α, IL-1β, and IL-6. These effects were partially reversed by ML385. Conclusion: Overexpression of MME mitigates oxidative stress and inflammation in painful diabetic neuropathy by activating the Nrf2/HO-1 signaling pathway.