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Nrf2 Suppression Delays Diabetic Wound Healing Through Sustained Oxidative Stress and Inflammation
Min Li1,2, Haibing Yu3,4, Haiyan Pan3
1Department of General Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China.
Abstract:
Impaired wound healing is one of the major complications of diabetes, involving prolonged inflammation, delayed re-epithelialization, and consistent oxidative stress. The detailed mechanism remains unclear, and there is currently no effective treatment for diabetic wound healing. In this study, we aim to investigate the potential role and effect of nuclear factor erythroid-2-related factor-2 (Nrf2) activation on diabetic wound healing. In vitro experiments in rat macrophages showed that hyperglycemia treatment suppresses Nrf2 activation, resulting in oxidative stress with decreased expression of antioxidant genes, including NAD(P)H:quinone oxidoreductase 1 and heme oxygenase 1, together with increased secretion of proinflammatory cytokines, including interleukin 1β (IL1β), IL6, and monocyte chemoattractant protein-1. Both Nrf2 overexpression and Nrf2 activator dimethyl fumarate (DMF) treatment significantly ameliorated oxidative stress and inflammation. On the other hand, both Nrf2 knockdown or Nrf2 inhibitor ML385 mimicked the effect of diabetes. Further in vivo experiments in rats showed that DMF treatment significantly accelerated wound healing in streptozocin-induced diabetic rats with increased expression of antioxidant enzymes and decreased secretion of proinflammatory cytokines, while Nrf2 inhibitor ML385 mimicked the effect of diabetes. We conclude that Nrf2 activation accelerates impaired wound healing by ameliorating diabetes-mediated oxidative stress and inflammation. This provides a new clinical treatment strategy for diabetic wound healing using Nrf2 activator DMF.
Insights
Nuclear factor erythroid-2-related factor-2 (Nrf2) activation improves diabetic wound healing by reducing oxidative stress and inflammation. Nrf2 activator dimethyl fumarate (DMF) shows promise as a new treatment strategy for diabetic complications.
Area of Science:
- Biomedical Science
- Molecular Biology
- Wound Healing Research
Background:
- Diabetes significantly impairs wound healing, characterized by prolonged inflammation, delayed re-epithelialization, and oxidative stress.
- The precise mechanisms underlying diabetic wound healing complications are not fully understood, necessitating novel therapeutic approaches.
- Current treatments for diabetic wound healing are limited, highlighting the need for effective strategies.
Purpose of the Study:
- To investigate the role and therapeutic effect of nuclear factor erythroid-2-related factor-2 (Nrf2) activation in diabetic wound healing.
- To elucidate how Nrf2 activation influences oxidative stress and inflammation in the context of diabetes-related wound complications.
Main Methods:
- In vitro studies using rat macrophages exposed to hyperglycemia to assess Nrf2 activation, oxidative stress markers, and inflammatory cytokine secretion.
- In vivo experiments utilizing streptozocin-induced diabetic rats to evaluate the impact of Nrf2 activator dimethyl fumarate (DMF) and Nrf2 inhibitor ML385 on wound healing.
- Analysis of antioxidant enzyme expression and proinflammatory cytokine levels in response to Nrf2 modulation.
Main Results:
- Hyperglycemia suppressed Nrf2 activation in vitro, leading to increased oxidative stress and pro-inflammatory cytokine release (IL1β, IL6, MCP-1).
- Nrf2 overexpression or DMF treatment ameliorated oxidative stress and inflammation in vitro.
- DMF treatment significantly accelerated wound healing in diabetic rats, accompanied by increased antioxidant enzyme expression and reduced inflammation.
- Nrf2 inhibition mimicked diabetic effects, while DMF treatment counteracted them.
Conclusions:
- Nrf2 activation effectively accelerates impaired diabetic wound healing.
- Nrf2 ameliorates diabetes-associated oxidative stress and inflammation, offering a potential therapeutic mechanism.
- Nrf2 activator DMF presents a promising new clinical strategy for treating diabetic wound healing complications.
