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.