Organ Protection by Caloric Restriction Depends on Activation of the De Novo NAD+ Synthesis Pathway.

Autor:	Späth MR; Department II of Internal Medicine and Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.; CECAD, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany., Hoyer-Allo KJR; Department II of Internal Medicine and Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.; CECAD, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany., Seufert L; Department II of Internal Medicine and Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.; CECAD, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany., Höhne M; Department II of Internal Medicine and Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany., Lucas C; CECAD, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany., Bock T; CECAD, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.; Institute of Genetics, University of Cologne, Cologne, Germany., Isermann L; CECAD, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.; Medical Faculty, Institute for Mitochondrial Diseases and Aging, University of Cologne, Cologne, Germany.; Center for Molecular Medicine (CMMC), University of Cologne, Cologne, Germany., Brodesser S; CECAD, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany., Lackmann JW; CECAD, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany., Kiefer K; Department II of Internal Medicine and Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.; CECAD, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany., Koehler FC; Department II of Internal Medicine and Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.; CECAD, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany., Bohl K; Department II of Internal Medicine and Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.; CECAD, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany., Ignarski M; Department II of Internal Medicine and Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.; CECAD, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany., Schiller P; Institute of Medical Statistics and Computational Biology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany., Johnsen M; Department II of Internal Medicine and Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.; CECAD, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany., Kubacki T; Department II of Internal Medicine and Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.; CECAD, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany., Grundmann F; Department II of Internal Medicine and Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany., Benzing T; Department II of Internal Medicine and Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.; CECAD, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany., Trifunovic A; CECAD, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.; Medical Faculty, Institute for Mitochondrial Diseases and Aging, University of Cologne, Cologne, Germany.; Center for Molecular Medicine (CMMC), University of Cologne, Cologne, Germany., Krüger M; CECAD, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.; Institute of Genetics, University of Cologne, Cologne, Germany.; Center for Molecular Medicine (CMMC), University of Cologne, Cologne, Germany., Schermer B; Department II of Internal Medicine and Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.; CECAD, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany., Burst V; Department II of Internal Medicine and Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.; Emergency Department, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany., Müller RU; Department II of Internal Medicine and Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.; CECAD, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
Jazyk:	angličtina
Zdroj:	Journal of the American Society of Nephrology : JASN [J Am Soc Nephrol] 2023 May 01; Vol. 34 (5), pp. 772-792. Date of Electronic Publication: 2023 Feb 09.
DOI:	10.1681/ASN.0000000000000087
Abstrakt:	Significance Statement: AKI is a major clinical complication leading to high mortality, but intensive research over the past decades has not led to targeted preventive or therapeutic measures. In rodent models, caloric restriction (CR) and transient hypoxia significantly prevent AKI and a recent comparative transcriptome analysis of murine kidneys identified kynureninase (KYNU) as a shared downstream target. The present work shows that KYNU strongly contributes to CR-mediated protection as a key player in the de novo nicotinamide adenine dinucleotide biosynthesis pathway. Importantly, the link between CR and NAD+ biosynthesis could be recapitulated in a human cohort. Background: Clinical practice lacks strategies to treat AKI. Interestingly, preconditioning by hypoxia and caloric restriction (CR) is highly protective in rodent AKI models. However, the underlying molecular mechanisms of this process are unknown. Methods: Kynureninase (KYNU) knockout mice were generated by Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) and comparative transcriptome, proteome and metabolite analyses of murine kidneys pre- and post-ischemia-reperfusion injury in the context of CR or ad libitum diet were performed. In addition, 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 effect 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 IRI and is essential for its full nephroprotective potential. Differential protein acetylation may be the molecular mechanism underlying the relationship of NAD+, CR, and nephroprotection. (Copyright © 2023 by the American Society of Nephrology.)
Databáze:	MEDLINE
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