Quercetin Ameliorates Diabetic Kidney Injury by Inhibiting Ferroptosis via Activating Nrf2/HO-1 Signaling Pathway
Quercetin Ameliorates Diabetic Kidney Injury by Inhibiting Ferroptosis via Activating Nrf2/HO-1 Signaling Pathway
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DOI：
10.1142/s0192415x23500465
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发表时间：
2023-04-10
影响因子：
5.7
通讯作者：
Liu, Zhangsuo
中科院分区：
文献类型：
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作者：
Feng, Qi;Yang, Yang;Liu, Zhangsuo
糖尿病肾病被认为是终末期肾病的主要原因。由于其复杂的发病机制和对糖尿病肾病治疗的低效率，深入了解新的病因可能是有用的。铁下垂是细胞死亡的一种非凋亡性形式，其特征是铁依赖的过氧化脂质积聚到致死水平。铁性下垂引发的肾小管损伤参与了糖尿病肾病的发生发展，阻断铁性下垂可能是预防糖尿病肾病发生的有效策略。栎素(QCT)是一种天然类黄酮，存在于多种水果和蔬菜中，已被报道可改善糖尿病肾病。然而，其潜在的肾脏保护机制尚不清楚。在此，我们利用糖尿病小鼠和高糖(HG)孵育的肾小管上皮细胞模型，探讨了清热通络片的抗铁上皮病作用，并验证了其对肾脏的保护作用。我们发现HG可引起肾小管上皮细胞铁下垂的异常激活，清热解毒汤通过下调肾小管上皮细胞转铁蛋白受体1(TFR-1)的表达，上调肾小管上皮细胞谷胱甘肽过氧化物酶4(Gpx4)、铁蛋白重链1(FTH-1)和胱氨酸/谷氨酸反向转运体溶质载体家族7成员(SLC7A11)的表达来抑制肾小管上皮细胞铁下垂。随后，体外和体内实验结果证实，清热解毒汤通过上调NRF2和HO-1的水平，激活了NFE2相关因子2(Nrf2)/血红素加氧酶-1(HO-1)信号通路。因此，本研究支持清肾通络片通过调节Nrf2/HO-1信号通路抑制肾小管上皮细胞铁性下垂，为探讨清热通络汤治疗糖尿病肾病的保护机制提供了新的思路。
Diabetic nephropathy (DN) is thought to be the major cause of end-stage renal disease. Due to its complicated pathogenesis and the low efficacy of DN treatment, a deep understanding of new etiological factors may be useful. Ferroptosis, a nonapoptotic form of cell death, is characterized by the accumulation of iron-dependent lipid peroxides to lethal levels. Ferroptosis-triggered renal tubular injury is reported to participate in the development of DN, and blocking ferroptosis might be an effective strategy to prevent the development of DN. Quercetin (QCT), a natural flavonoid that is present in a variety of fruits and vegetables, has been reported to ameliorate DN. However, its underlying nephroprotective mechanism is unclear. Herein, we explored the antiferroptosic effect of QCT and verified its nephroprotective effect using DN mice and high glucose (HG)-incubated renal tubular epithelial cell models. We found HG-induced abnormal activation of ferroptosis of renal tubular epithelial cells, and QCT treatment inhibited ferroptosis by downregulating the expression of transferrin receptor 1 (TFR-1) and upregulating the expression of glutathione peroxidase 4 (GPX4), ferritin heavy chain 1 (FTH-1), and the cystine/glutamate reverse antiporter solute carrier family 7 member (SLC7A11) in DN mice and HG-incubated HK-2 cells. Subsequently, both in vitro and in vivo results confirmed that QCT activated the NFE2-related factor 2 (Nrf2)/Heme oxygenase-1(HO-1) signaling pathway by increasing the levels of Nrf2 and HO-1. Therefore, this study supports that QCT inhibits the ferroptosis of renal tubular epithelial cells by regulating the Nrf2/HO-1 signaling pathway, providing a novel insight into the protective mechanism of QCT in DN treatment.