Endothelial prostacyclin protects the kidney from ischemia-reperfusion injury.

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.

Nicotinamide Mononucleotide, an NAD+ Precursor, Rescues Age-Associated Susceptibility to AKI in a Sirtuin 1-Dependent Manner.

The rapid growth of an aging population creates challenges regarding age-related diseases, including AKI, for which both the prevalence and death rate increase with age. The molecular mechanism by which the aged kidney becomes more susceptible to acute injury has not been completely elucidated. In this study, we found that, compared with the kidneys of 3-month-old mice, the kidneys of 20-month-old mice expressed reduced levels of the renal protective molecule sirtuin 1 (SIRT1) and its cofactor NAD+ Supplementation with nicotinamide mononucleotide (NMN), an NAD+ precursor, restored renal SIRT1 activity and NAD+ content in 20-month-old mice and further increased both in 3-month-old mice. Moreover, supplementation with NMN significantly protected mice in both age groups from cisplatin-induced AKI. SIRT1 deficiency blunted the protective effect of NMN, and microarray data revealed that c-Jun N-terminal kinase (JNK) signaling activation associated with renal injury in SIRT1 heterozygotes. In vitro, SIRT1 attenuated the stress response by modulating the JNK signaling pathway, probably via the deacetylation of a JNK phosphatase, DUSP16. Taken together, our findings reveal SIRT1 as a crucial mediator in the renal aging process. Furthermore, manipulation of SIRT1 activity by NMN seems to be a potential pharmaceutical intervention for AKI that could contribute to the precise treatment of aged patients with AKI.