Inhibition of 15-PGDH prevents ischemic renal injury by the PGE<sub>2</sub>/EP<sub>4</sub>signaling pathway mediating vasodilation, increased renal blood flow, and increased adenosine/A<sub>2A</sub>receptors
Hye Jung Kim, Sun‐Hee Kim, Min‐Jung Kim, HyungJoo Baik, Seok Ju Park, Mi Seon Kang, Dong‐Hyun Kim, Byeong Woo Kim, Sanford D. Markowitz, Ki Beom Bae
Abstract
In the present study, we demonstrated the marked activity of SW033291, an inhibitor of 15-hydoxyprostaglandin dehydrogenase (15-PGDH), in preventing acute kidney injury (AKI) in a murine model of ischemia-reperfusion injury. AKI due to ischemic injury represents a significant clinical problem. PGE 2 is vasodilatory in the kidney, but it is rapidly degraded in vivo due to catabolism by 15-PGDH. We investigated the potential of SW033291, a potent and specific 15-PGDH inhibitor, as prophylactic treatment for ischemic AKI. Prophylactic administration of SW033291 significantly increased renal tissue PGE 2 levels and increased post-AKI renal blood flow and renal arteriole area. In parallel, prophylactic SW033291 decreased post-AKI renal morphology injury scores and tubular apoptosis and markedly reduced biomarkers of renal injury that included blood urea nitrogen, creatinine, neutrophil gelatinase-associated lipocalin, and kidney injury molecule-1. Prophylactic SW033291 also reduced post-AKI induction of proinflammatory cytokines, high-mobility group box 1, and malondialdehyde. Protective effects of SW033291 were mediated by PGE 2 signaling, as they could be blocked by pharmacological inhibition of PGE 2 synthesis. Consistent with activation of PGE 2 signaling, SW033291 induced renal levels of both EP 4 receptors and cAMP, along with other vasodilatory effectors, including AMP, adenosine, and the adenosine A 2A receptor. The protective effects of SW0333291 could largely be achieved with a single prophylactic dose of the drug. Inhibition of 15-PGDH may thus represent a novel strategy for prophylaxis of ischemic AKI in multiple clinical settings, including renal transplantation and cardiovascular surgery.