Inhibition of ferroptosis by up-regulating Nrf2 delayed the progression of diabetic nephropathy
Inhibition of ferroptosis by up-regulating Nrf2 delayed the progression of diabetic nephropathy
复制标题
通过上调Nrf2抑制铁死亡延缓糖尿病肾病的进展
DOI：
10.1016/j.freeradbiomed.2020.10.323
复制
发表时间：
2021-02-13
影响因子：
7.4
通讯作者：
Wu, Zhongming
中科院分区：
文献类型：
--
作者：
Li, Shuangwen;Zheng, Lisi;Wu, Zhongming
糖尿病肾病（DN）是目前公认的终末期肾病的主要病因。在糖尿病中，活性氧（ROS）的积累和铁超载是促进DN发生的重要决定因素。然而，它们如何引起糖尿病肾损害的潜在机制仍不清楚。以铁依赖性脂质过氧化为特征的铁凋亡为我们研究DN的进展提供了新的思路。链脲佐菌素（STZ）诱导的DBA/2 J糖尿病小鼠肾脏和高糖培养的人近端肾小管（HK-2）细胞均出现铁超载、抗氧化能力下降、大量活性氧（ROS）和脂质过氧化反应，是铁凋亡的标志性改变。此外，在高糖培养的细胞中观察到特征性的线粒体形态学变化。在DN模型中，铁蛋白抑制素-1（Ferrostatin-1，Fer-1）的额外治疗显著地挽救了这些改变，并且减轻了糖尿病小鼠的肾脏病理损伤。此外，在DN模型中观察到NFE 2相关因子2（Nrf 2）降低。Nrf 2的特异性敲低增加了细胞在高糖条件下对铁凋亡的敏感性。在Nrf 2敲低的细胞中，通过用非诺贝特处理上调Nrf 2改善了铁凋亡的情况，这在RSL-3诱导的细胞中得到证实。此外，Nrf 2的增加可抑制糖尿病小鼠的铁凋亡相关变化，从而延缓DN的进展。总的来说，我们证明了铁凋亡参与了DN的发展，通过非诺贝特治疗上调Nrf 2抑制了糖尿病相关的铁凋亡，延缓了DN的进展。本研究从一个新的角度揭示了DN的发生发展机制，为延缓DN的进展提供了新的途径。
Diabetic nephropathy (DN) is now considered the leading cause of end-stage renal disease. In diabetes, the accumulation of reactive oxygen species (ROS) and iron overload are important determinants that promote the occurrence of DN. However, the underlying mechanism of how they cause diabetic kidney damage remains unclear. Ferroptosis, characterized by iron-dependent lipid peroxidation, provided us with a new idea to explore the progression of DN. Iron overload, reduced antioxidant capability, massive ROS and lipid peroxidation were detected in the kidneys of streptozotocin-induced DBA/2J diabetic mice and high-glucose cultured human renal proximal tubular (HK-2) cells, which were the symbolic changes of ferroptosis. Furthermore, the characteristic mitochondrial morphological changes of ferroptosis were observed in high glucose cultured cells. Additional treatment of Ferrostatin-1 (Fer-1) in DN models significantly rescued these changes and alleviated the renal pathological injuries in diabetic mice. Besides, the decreased NFE2-related factor 2 (Nrf2) was observed in DN models. The specific knockdown of Nrf2 increased the sensitivity of cells to ferroptosis in the high glucose condition. In Nrf2 knockdown cells, up-regulating Nrf2 by treating with fenofibrate improved the situation of ferroptosis, which was verified in RSL-3 induced cells. Moreover, the ferroptosis-related changes were inhibited by increasing Nrf2 in fenofibrate treated diabetic mice, which delayed the progression of DN. Collectively, we demonstrated that ferroptosis was involved in the development of DN, and up-regulating Nrf2 by treating with fenofibrate inhibited diabetes-related ferroptosis, delaying the progression of DN. Our research revealed the development mechanism of DN from a new perspective, and provide a new approach delaying the progression of DN.