PGE2 pathway mediates oxidative stress‐induced ferroptosis in renal tubular epithelial cells

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 H2O2, 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, Fe2+ 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.

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