Liu Ying, Zhou Lin, Lv Caihong, Liu Lingyun, Miao Shuying, Xu Yunfei, Li Kexin, Zhao Yao, Zhao Jie
Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China.
Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, China.
FEBS J. 2023 Jan;290(2):533-549. doi: 10.1111/febs.16609. Epub 2022 Oct 13.
Prostaglandin E2 (PGE2) is one of the most abundant prostaglandins and has been implicated in various diseases. Here, we aimed to explore the role of the PGE2 pathway in mediating ferroptosis during acute kidney injury. When renal tubular epithelial cells stimulated by H O , the contents of glutathione (GSH) and glutathione peroxidase 4 (GPX4) decreased, whereas the level of lipid peroxide increased. Ferrostatin-1 can effectively attenuate these changes. In this process, the expression levels of cyclooxygenase (COX)-1 and COX-2 were up-regulated. Meanwhile, the expression of microsomal prostaglandin E synthase-2 was elevated, whereas the expression of microsomal prostaglandin E synthase-1 and cytosolic prostaglandin E synthase were down-regulated. Furthermore, the expression of 15-hydroxyprostaglandin dehydrogenase decreased. An excessive accumulation of PGE2 promoted ferroptosis, whereas the PGE2 inhibitor pranoprofen minimized the changes for COX-2, GSH, GPX4 and lipid peroxides. A decrease in the levels of the PGE2 receptor E-series of prostaglandin 1/3 partially restored the decline of GSH and GPX4 levels and inhibited the aggravation of lipid peroxide. Consistent with the in vitro results, increased PGE2 levels led to increased levels of 3,4-methylenedioxyamphetamine, Fe accumulation and decreased GSH and GPX4 levels during renal ischaemia/reperfusion injury injury in mice. Our results indicate that the PGE2 pathway mediated oxidative stress-induced ferroptosis in renal tubular epithelial cells.
前列腺素E2（PGE2）是最丰富的前列腺素之一，与多种疾病有关。在此，我们旨在探讨PGE2途径在急性肾损伤中介导铁死亡的作用。当肾小管上皮细胞受到H₂O₂刺激时，谷胱甘肽（GSH）和谷胱甘肽过氧化物酶4（GPX4）的含量降低，而脂质过氧化物水平升高。铁死亡抑制剂1可以有效减轻这些变化。在此过程中，环氧化酶（COX）-1和COX-2的表达水平上调。同时，微粒体前列腺素E合酶-2的表达升高，而微粒体前列腺素E合酶-1和胞质前列腺素E合酶的表达下调。此外，15-羟基前列腺素脱氢酶的表达降低。PGE2的过度积累促进了铁死亡，而PGE2抑制剂普拉洛芬可使COX-2、GSH、GPX4和脂质过氧化物的变化最小化。前列腺素E系列受体1/3水平的降低部分恢复了GSH和GPX4水平的下降，并抑制了脂质过氧化物的加重。与体外结果一致，在小鼠肾缺血/再灌注损伤期间，PGE2水平升高导致3,4-亚甲基二氧安非他明水平升高、铁积累以及GSH和GPX4水平降低。我们的结果表明，PGE2途径介导了肾小管上皮细胞中氧化应激诱导的铁死亡。
