Macrovascular complications develop in over a half of the diabetic individuals, resulting in high morbidity and mortality. This poses a severe threat to public health and a heavy burden to social economy. It is therefore important to develop effective approaches to prevent or slow down the pathogenesis and progression of macrovascular complications of diabetes (MCD). Oxidative stress is a major contributor to MCD. Nuclear factor (erythroid‐derived 2)‐like 2 (NRF2) governs cellular antioxidant defence system by activating the transcription of various antioxidant genes, combating diabetes‐induced oxidative stress. Accumulating experimental evidence has demonstrated that NRF2 activation protects against MCD. Structural inhibition of Kelch‐like ECH‐associated protein 1 (KEAP1) is a canonical way to activate NRF2. More recently, novel approaches, such as activation of the Nfe2l2 gene transcription, decreasing KEAP1 protein level by microRNA‐induced degradation of Keap1 mRNA, prevention of proteasomal degradation of NRF2 protein and modulation of other upstream regulators of NRF2, have emerged in prevention of MCD. This review provides a brief introduction of the pathophysiology of MCD and the role of oxidative stress in the pathogenesis of MCD. By reviewing previous work on the activation of NRF2 in MCD, we summarize strategies to activate NRF2, providing clues for future intervention of MCD. Controversies over NRF2 activation and future perspectives are also provided in this review.

中文翻译：

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NRF2在糖尿病大血管并发症中的保护作用。

一半以上的糖尿病患者出现大血管并发症，导致高发病率和高死亡率。这对公共卫生构成了严重威胁，并给社会经济带来沉重负担。因此，重要的是开发有效的方法来预防或减慢糖尿病大血管并发症（MCD）的发病机理和进展。氧化应激是导致MCD的主要因素。核因子（类胡萝卜素衍生的2）样2（NRF2）通过激活各种抗氧化剂基因的转录来控制细胞抗氧化剂防御系统，从而对抗糖尿病引起的氧化应激。越来越多的实验证据表明NRF2激活可防止MCD。对Kelch样ECH相关蛋白1（KEAP1）的结构抑制是激活NRF2的典型方法。最近，新颖的方法Nfe2l2基因转录，通过microRNA诱导的Keap1 mRNA降解降低KEAP1蛋白水平，预防NRF2蛋白的蛋白酶体降解以及调节NRF2的其他上游调节剂，已成为预防MCD的新方法。这篇综述简要介绍了MCD的病理生理以及氧化应激在MCD发病机理中的作用。通过回顾以前在MCD中激活NRF2的工作，我们总结了激活NRF2的策略，为MCD的未来干预提供了线索。在这篇评论中也提供了关于NRF2激活的争议和未来的观点。