Pretreatment with Roxadustat (FG-4592) Attenuates Folic Acid-Induced Kidney Injury through Antiferroptosis via Akt/GSK-3β/Nrf2 Pathway
Pretreatment with Roxadustat (FG-4592) Attenuates Folic Acid-Induced Kidney Injury through Antiferroptosis via Akt/GSK-3β/Nrf2 Pathway
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DOI：
10.1155/2020/6286984
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发表时间：
2020-01-20
影响因子：
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通讯作者：
Zhai, Xiao-Yue
中科院分区：
文献类型：
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作者：
Li, Xue;Zou, Yu;Zhai, Xiao-Yue
叶酸（FA-）引起的肾损伤的特征是由于抗氧化系统的紊乱而引起的小管损伤和随后的间质纤维化。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。本研究探讨FG-4592预处理在肾损伤早期的保护作用及对肾纤维化进展的长期影响。FG-4592在小鼠FA注射前2天给药。注射FA后第2天，经FG-4592预处理的小鼠与未经FG-4592预处理的小鼠相比，在生化和组织学指标上表现出肾功能的改善；同时，细胞铁、丙二醛和4-羟基壬烯醛含量在组织学上降低，表明铁积累和脂质过氧化受到抑制。同时，HIF-1 α上调，Nrf2激活，核易位增加，下游蛋白高表达，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。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预处理降低了发生铁下垂的风险。这一点被fa处理的小鼠在给予铁他汀-1（一种特异性铁下垂抑制剂）治疗后的病理参数逆转和肾功能改善所证实。此外，一项信号通路研究表明，Nrf2激活与Akt和GSK-3 β磷酸化增加有关，这一点通过使用磷酸化Akt的PI3K抑制剂得到了证实。此外，FG-4592预处理还能降低巨噬细胞的浸润和炎症因子tnf - α和IL-1 β的表达。注射FA后第14天，FG-4592预处理可降低胶原沉积和纤维化生物标志物的表达。上述研究结果表明，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，在fa诱导的肾损伤早期减少铁凋亡，从而延缓纤维化进程。
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-1 alpha 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-3 beta, 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-alpha and IL-1 beta. 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-3 beta-mediated Nrf2 activation, which retards the fibrosis progression.