Endothelial prostacyclin protects the kidney from ischemia-reperfusion injury

Prostacyclin, or PGI(2), is a product of PGI synthase (PGIS), down-stream of cyclooxygenase pathway. PGI(2) has been demonstrated to play an important role in maintaining renal blood flow. Non-steroidal anti-inflammatory drugs (NSAIDs) that inhibit cyclooxygenase are reported to increase the susceptibility of patients to acute kidney injury (AKI). This study explores the role of endothelium-derived prostacyclin in ischemia-reperfusion injury (I/RI). The renal PGIS expression and PGI(2) production markedly increased following I/RI. Loss of one allele of PGIS gene or selective endothelial PGIS deletion (TEK-CRE PGIS(fl/fl) mice) caused more severe renal damage following I/RI than control mice. Iloprost, a PGI(2) analog, administered 30 min before the I/R surgery, markedly attenuated the renal damage in both control mice and TEK-CRE PGIS(fl/fl) mice. Renal p-PKA expression significantly increased after I/RI in wild-type mice but not in the PGIS deletion mice, consistent with IP receptor mediating the protective effect. Further studies showed that PGIS deficiency was associated with reduced fluorescence microsphere accumulation in the kidney following I/R. Folic acid also induced marked kidney injury; however, endothelial PGIS deletion did not worsen kidney injury compared with wild-type mice. These studies indicate that PGIS-derived PGI(2) can protect the kidney from acute injury caused by ischemia and reperfusion and PGIS/PGI(2) is a potential intervention target for AKI.