J Am Soc Nephrol. 2023 Feb 9. doi: 10.1681/ASN.0000000000000087. Online ahead of print.
ABSTRACT
BACKGROUND: Clinical practice lacks strategies to treat acute kidney injury (AKI). Interestingly, preconditioning by hypoxia (HP) and caloric restriction (CR) is highly protective in rodent AKI models. However, the underlying molecular mechanisms of this process are unknown.
METHODS: CRISPR generated kynureninase (KYNU) knockout mice and comparative transcriptome, proteome, and metabolite analyses of murine kidneys (C57Bl6N wild type and KYNU-deficient) pre- and post-ischemia-reperfusion injury, in the context of CR or ad libitum diet, performed. Additionally, acetyl-lysin enrichment and mass spectrometry were used to assess protein acetylation..
RESULTS: We identified KYNU as a downstream target of CR and show that KYNU strongly contributes to the protective effect of CR. The KYNU-dependent de novo nicotinamide adenine dinucleotide (NAD+) biosynthesis pathway is necessary for CR-associated maintenance of NAD+ levels. This finding is associated with reduced protein acetylation in CR-treated animals, specifically affecting enzymes in energy metabolism. Importantly, the impact of CR on de novo NAD+ biosynthesis pathway metabolites can be recapitulated in humans.
CONCLUSIONS: CR induces the de novo NAD+ synthesis pathway in the context of Ischemia-reperfusion injury and is essential for its full nephroprotective potential. Differential protein acetylation may be the molecular mechanism underlying the relationship of NAD+, CR, and nephroprotection.
PMID:36758124 | DOI:10.1681/ASN.0000000000000087
