NAD ameliorates endotoxin-induced acute kidney injury in a sirtuin1-dependent manner via GSK-3β/Nrf2 signalling pathway.

Acute kidney injury (AKI) is a substantial worldwide public health concern with no specific and effective therapies in clinic. NAD is a pivotal determinant of cellular energy metabolism involved in the progression of AKI; however, its mechanism in kidney injury remains poorly understood. Sirtuin 1 (SIRT1) is an NAD -dependent deacetylase associated with renal protection and acute stress resistance. In this study, we have investigated the role of NAD in AKI and the potential mechanism(s) involved in its renoprotective effect. NAD was notably decreased and negatively correlated with kidney dysfunction in AKI, restoring NAD with NMN significantly ameliorates LPS-induced oxidative stress and apoptosis and attenuates renal damage. We also found that the protection of NAD is associated with SIRT1 expressions and performs in a SIRT1-dependent manner. Inhibition of SIRT1 blunted the protective effect of NAD and up-regulated the activity of glycogen synthase kinase-3β (GSK-3β) that was concomitant with mitigated Nrf2 nuclear accumulation, thereby exacerbates AKI. These findings suggest that NAD /SIRT1/GSK-3β/Nrf2 axis is an important mechanism that can protect against AKI which might be a potential therapeutic target for the treatment of AKI.