Organ protection by caloric restriction depends on activation of the de novo NAD+ synthesis pathway

Therapeutic strategies to treat acute kidney injury (AKI) are lacking. Preconditioning by hypoxia (HP) and caloric restriction (CR) is highly protective in rodent AKI models. The underlying molecular mechanisms are unknown. A comparative transcriptome analysis after HP and CR identified Kynureninase (KYNU) as a common downstream target. Using a newly generated KYNU-deficient mouse line, we show that KYNU contributes to the protective effect of preconditioning. Metabolome, transcriptome and proteome analyses reveal KYNU as necessary for CR-associated maintenance of nicotinamide adenine dinucleotide (NAD+) levels. Importantly, the impact of CR on the de novo NAD+ biosynthesis pathway can be recapitulated in humans.