Abstract
Prostacyclin, or PGI2, is a product of PGI synthase (PGIS), down-stream of cyclooxygenase pathway. PGI2 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 PGI2 production markedly increased following I/RI. Loss of one allele of PGIS gene or selective endothelial PGIS deletion (TEK-CRE PGISfl/fl mice) caused more severe renal damage following I/RI than control mice. Iloprost, a PGI2 analog, administered 30 min before the I/R surgery, markedly attenuated the renal damage in both control mice and TEK-CRE PGISfl/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 PGI2 can protect the kidney from acute injury caused by ischemia and reperfusion and PGIS/PGI2 is a potential intervention target for AKI.
Highlights
Acute kidney injury (AKI) is a global public concern that is associated with high morbidity, mortality, and healthcare costs, and is increasingly prevalent in both developing and developed countries [24, 27, 42]
We demonstrated that (1) I/R stimulated the expression of PGI synthase (PGIS) and PGI2; (2) global PGIS deficiency or endothelial-specific PGIS deletion exacerbated I/R-induced injuries; (3) an exogenous PGI2 analog protected the kidney from I/R-induced injury; and (4) PGI2 deficiency was associated with reduced renal blood flow following reperfusion
These results strongly suggest that endothelium-derived PGI2 plays a critical role in protecting the kidney from I/R injury
Summary
Acute kidney injury (AKI) is a global public concern that is associated with high morbidity, mortality, and healthcare costs, and is increasingly prevalent in both developing and developed countries [24, 27, 42]. Ischemia-reperfusion injury (I/RI) is the most common cause of AKI [2, 43]. Extensive studies have been performed over the past decades, the incidence of AKI remains high, and therapies are limited. Renal I/RI is almost unavoidable in renal transplantation [25], which may contribute significantly to delayed graft function (DGF). Up to 30% of the patients receiving cardiac surgery may experience acute kidney injury [36]. No pharmacological treatments reliably improve survival, limit injury, or accelerate recovery [47]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
