Necroinflammation plays an important role in disease settings such as acute kidney injury (AKI). We and others have elucidated that prostaglandins, which are critically involved in inflammation, may activate E-prostanoid 3 receptor (EP3) at low concentrations. However, how EP3 blockade interacts with regulated cell death and affects AKI remains unknown. In this study, AKI was induced by ischemia-reperfusion (30 minutes/24 hours) in Ep3 knockout (Ep3-/-), bone marrow chimeric, myeloid conditional EP3 knockout and corresponding control mice. The production of prostaglandins E2 and I2 was markedly increased after ischemia-reperfusion, and either abrogation or antagonism of EP3 ameliorated the injury. EP3 deficiency curbed inflammatory cytokine release, neutrophil infiltration and serum high-mobility group box 1 levels, but additional TLR4 inhibition with TAK-242 did not offer further protection against the injury and inflammation. The protection of Ep3-/- was predominantly mediated by suppressing Mixed Lineage Kinase domain-Like-dependent necroptosis, resulting from the inhibition of cytokine generation and the switching of cell death modality from necroptosis to apoptosis through caspase-8 up-regulation, in part due to the restraint of IL-6/JAK2/STAT3 signaling. EP3 deficiency failed to further alleviate the injury when necroptosis was inhibited. Ep3-/- in bone marrow-derived cells, particularly that in myeloid cells, protected kidneys to the same extent as that of global EP3 deletion. Thus, our results demonstrate that EP3 deficiency especially that on myeloid cells, ameliorates ischemic AKI via curbing inflammation and breaking the auto-amplification loop of necroinflammation. Hence, EP3 may be a promising target for the prevention and/or treatment of AKI.
Keywords: acute kidney injury; caspase-8; inflammation; prostaglandin; regulated necrosis.
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