Roxadustat (FG-4592) 预处理通过 Akt/GSK-3β/Nrf2 通路通过抗铁死亡减轻叶酸诱导的肾脏损伤。,Oxidative Medicine and Cellular Longevity

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Roxadustat (FG-4592) 预处理通过 Akt/GSK-3β/Nrf2 通路通过抗铁死亡减轻叶酸诱导的肾脏损伤。
Oxidative Medicine and Cellular Longevity Pub Date : 2020-01-20 , DOI: 10.1155/2020/6286984
Xue Li _{1,

2} , Yu Zou ₁ , Jia Xing ₁ , Yuan-Yuan Fu ₁ , Kai-Yue Wang ₁ , Peng-Zhi Wan ₃ , Xiao-Yue Zhai _{1,

4}

Affiliation

叶酸（FA-）诱导的肾损伤的特征是由于抗氧化系统的紊乱和随后的间质纤维化导致的肾小管损伤。FG-4592 是一种抗氧化因子缺氧诱导因子 (HIF) 脯氨酰羟化酶抑制剂。本研究调查了 FG-4592 预处理在肾损伤早期的保护作用以及对肾纤维化进展的长期影响。FG-4592 在小鼠 FA 注射前两天给药。在 FA 注射后的第二天，与未进行 FG-4592 预处理的小鼠相比，经 FG-4592 预处理的小鼠肾功能有所改善，生化和组织学参数表明；同时，组织学上铁、丙二醛和 4-羟基壬烯醛的细胞含量降低，这意味着铁积累和脂质过氧化的抑制。同时，HIF-1 上调发现了α以及 Nrf2 激活，这反映在核转位增加和下游蛋白（包括血红素加氧酶 1、谷胱甘肽过氧化物酶 4、胱氨酸/谷氨酸转运蛋白以及铁转运蛋白）的高表达上。相应地，观察到抗氧化酶和谷胱甘肽水平升高，铁积累减少，表明 FG-4592 预处理后发生铁死亡的风险较低。使用 ferrostatin-1（一种特定的铁死亡抑制剂）治疗 FA 的小鼠逆转了病理参数并改善了肾功能，证实了这一点。此外，一项信号通路研究表明，Nrf2 激活与 Akt 和 GSK-3 β 的磷酸化增加有关，通过使用磷酸化 Akt 的 PI3K 抑制剂来验证。此外，FG-4592 预处理还降低了巨噬细胞浸润和炎症因子 TNF - α和 IL-1 β 的表达。在14^个FA注射后一天，FG-4592预处理减少胶原沉积和纤维化的生物标志物的表达。这些发现表明，FG-4592 预处理的保护作用主要是通过 Akt/GSK-3 β介导的 Nrf2 激活来减少 FA 诱导的肾损伤早期的铁死亡，从而延缓纤维化进展。

"点击查看英文标题和摘要"

Pretreatment with Roxadustat (FG-4592) Attenuates Folic Acid-Induced Kidney Injury through Antiferroptosis via Akt/GSK-3β/Nrf2 Pathway.

Folic acid- (FA-) induced kidney injury is characterized by the tubule damage due to the disturbance of the antioxidant system and subsequent interstitial fibrosis. FG-4592 is an inhibitor of prolyl hydroxylase of hypoxia-inducible factor (HIF), an antioxidant factor. The present study investigated the protective role of FG-4592 pretreatment at the early stage of the kidney injury and long-term impact on the progression of renal fibrosis. FG-4592 was administrated two days before FA injection in mice. On the second day after FA injection, the mice with FG-4592 pretreatment showed an improved renal function, compared with those without FG-4592 pretreatment, indicated by biochemical and histological parameters; meanwhile, the cellular content of iron, malondialdehyde, and 4-hydroxynonenal histologically decreased, implying the suppression of iron accumulation and lipid peroxidation. Simultaneously, upregulation of HIF-1α was found, along with Nrf2 activation, which was reflected by increased nuclear translocation and high-expression of downstream proteins, including heme-oxygenase1, glutathione peroxidase4, and cystine/glutamate transporter, as well as ferroportin. Correspondingly, the elevated levels of antioxidative enzymes and glutathione, as well as reduced iron accumulation, were observed, suggesting a lower risk of occurrence of ferroptosis with FG-4592 pretreatment. This was confirmed by reversed pathological parameters and improved renal function in FA-treated mice with the administration of ferrostatin-1, a specific ferroptosis inhibitor. Furthermore, a signal pathway study indicated that Nrf2 activation was associated with increased phosphorylation of Akt and GSK-3β, verified by the use of an inhibitor of the PI3K that phosphorylates Akt. Moreover, FG-4592 pretreatment also decreased macrophage infiltration and expression of inflammatory factors TNF-α and IL-1β. On the 14^th day after FA injection, FG-4592 pretreatment decreased collagen deposition and expression of fibrosis biomarkers. These findings suggest that the protective role of FG-4592 pretreatment is achieved mainly by decreasing ferroptosis at the early stage of FA-induced kidney injury via Akt/GSK-3β-mediated Nrf2 activation, which retards the fibrosis progression.

更新日期：2020-01-20

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