An Essential Role of NRF2 in Diabetic Wound Healing.
An Essential Role of NRF2 in Diabetic Wound Healing.
复制标题
NRF2 在糖尿病伤口愈合中的重要作用。
作者：
Long M;Rojo de la Vega M;Wen Q;Bharara M;Jiang T;Zhang R;Zhou S;Wong PK;Wondrak GT;Zheng H;Zhang DD
糖尿病无法愈合的皮肤溃疡的高死亡率和致残率迫切需要开发更有效的针对糖尿病伤口愈合的策略。在目前的研究中，我们利用人类临床标本显示，糖尿病患者的皮损周围皮肤组织比正常血糖患者的皮损周围皮肤组织处于更严重的氧化应激下，并且表现出更高的核因子-E2相关因子2(NRF2)介导的抗氧化反应的激活。在链脲佐菌素诱导的糖尿病小鼠模型中，与NRF2+/+小鼠相比，NRF2−/−小鼠的伤口闭合率延迟，这至少部分是由于更大的氧化β损伤，低转化生长因子-β1和高基质金属蛋白酶9的表达，以及增加细胞凋亡。更重要的是，NRF2通路的药理激活显著促进了糖尿病伤口的愈合。体外培养的人永生化角质形成细胞实验证实，在高糖条件下，NRF2通过减轻氧化应激，促进增殖和迁移，减少细胞凋亡，增加转化生长因子-β1的表达，降低基质金属蛋白酶9的表达，促进伤口愈合。这项研究表明了NRF2在糖尿病伤口愈合中的重要作用，以及激活NRF2在这种疾病中的治疗作用，为未来使用NRF2激活剂治疗糖尿病皮肤溃疡的临床试验奠定了基础。
The high mortality and disability of diabetic nonhealing skin ulcers create an urgent need for the development of more efficacious strategies targeting diabetic wound healing. In the current study, using human clinical specimens, we show that perilesional skin tissues from patients with diabetes are under more severe oxidative stress and display higher activation of the nuclear factor-E2–related factor 2 (NRF2)–mediated antioxidant response than perilesional skin tissues from normoglycemic patients. In a streptozotocin-induced diabetes mouse model, Nrf2−/− mice have delayed wound closure rates compared with Nrf2+/+ mice, which is, at least partially, due to greater oxidative DNA damage, low transforming growth factor-β1 (TGF-β1) and high matrix metalloproteinase 9 (MMP9) expression, and increased apoptosis. More importantly, pharmacological activation of the NRF2 pathway significantly improves diabetic wound healing. In vitro experiments in human immortalized keratinocyte cells confirm that NRF2 contributes to wound healing by alleviating oxidative stress, increasing proliferation and migration, decreasing apoptosis, and increasing the expression of TGF-β1 and lowering MMP9 under high-glucose conditions. This study indicates an essential role for NRF2 in diabetic wound healing and the therapeutic benefits of activating NRF2 in this disease, laying the foundation for future clinical trials using NRF2 activators in treating diabetic skin ulcers.