Shan Kai, Li Jiaqi, Yang Qin, Chen Kang, Zhou Shanshan, Jia Lingling, Fu Guoling, Qi Yumin, Wang Qizai, Chen Yong Q
College of Food Science and Technology, Nanjing Agricultural University, Nanjing, Jiangsu Province, China.
Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu Province, China; School of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu Province, China.
J Nutr Biochem. 2023 Oct;120:109418. doi: 10.1016/j.jnutbio.2023.109418. Epub 2023 Jul 23.
Ferroptosis due to polyunsaturated fatty acid (PUFA) peroxidation has been implicated in the pathogenesis of acute kidney injury (AKI), suggesting the risk of dietary intake of PUFA for people susceptible to AKI. Clinically, however, in addition to ferroptosis, other mechanisms also contribute to different types of AKI such as inflammation associated necroptosis and pyroptosis. Therefore, the role of PUFA, especially ω3 PUFA which is a common food supplement, in various AKIs deserves further evaluation. In this study, rhabdomyolysis- and folic acid-induced AKI (Rha-AKI and FA-AKI) were established in mice fed with different fatty acids Histology of kidney, blood urea nitrogen and creatinine, lipid peroxidation, and inflammatory factors were examined. Results showed that these two types of AKIs had diametrically different pathogenesis indicated by that ferrostatin-1 (Fer-1), a lipid antioxidant, can attenuate FA-AKI rather than Rha-AKI. Further, dietary DHA (provided by fish oil) reduced tubular injury and renal lesion by inhibiting peroxidation and inflammation in mice with Rha-AKI while increasing cell death, tissue damage, peroxidation and inflammation in mice with FA-AKI. In human renal tubular epithelial cell line HK-2, MTT assay and DHE staining showed that both myoglobin and ferroptosis inducers can cause cell death and oxidative stress. Ferroptosis inducer-induced cell death was promoted by DHA, while such result was not observed in myoglobin-induced cell death when adding DHA. This study illustrates that the mechanisms of AKI might be either ferroptosis dependent or -independent and the deterioration effect of dietary DHA depends on whether ferroptosis is involved.
多不饱和脂肪酸（PUFA）过氧化引起的铁死亡与急性肾损伤（AKI）的发病机制有关，这表明易患AKI的人群存在膳食摄入PUFA的风险。然而，在临床上，除铁死亡外，其他机制也导致不同类型的AKI，如炎症相关的坏死性凋亡和细胞焦亡。因此，PUFA，尤其是作为常见食品补充剂的ω3 PUFA，在各种AKI中的作用值得进一步评估。在本研究中，在喂食不同脂肪酸的小鼠中建立了横纹肌溶解和叶酸诱导的AKI（Rha-AKI和FA-AKI）模型。检测了肾脏组织学、血尿素氮和肌酐、脂质过氧化和炎症因子。结果表明，这两种类型的AKI具有截然不同的发病机制，脂质抗氧化剂铁抑素-1（Fer-1）可减轻FA-AKI而非Rha-AKI即可证明。此外，膳食二十二碳六烯酸（DHA，由鱼油提供）通过抑制Rha-AKI小鼠的过氧化和炎症反应减轻肾小管损伤和肾脏病变，而在FA-AKI小鼠中则增加细胞死亡、组织损伤、过氧化和炎症反应。在人肾小管上皮细胞系HK-2中，MTT法和DHE染色显示，肌红蛋白和铁死亡诱导剂均可导致细胞死亡和氧化应激。DHA促进铁死亡诱导剂诱导的细胞死亡，而添加DHA时在肌红蛋白诱导的细胞死亡中未观察到此结果。本研究表明，AKI的机制可能依赖或不依赖于铁死亡，膳食DHA的恶化作用取决于是否涉及铁死亡。
