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Kidney Week

Abstract: PO0354

Kidney Protection by Caloric Restriction Depends on De Novo NAD+ Synthesis Activation

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Späth, Martin R., Department II of Internal Medicine, University hospital of Cologne, Cologne, Germany
  • Hoyer-Allo, Karla Johanna Ruth, Department II of Internal Medicine, University hospital of Cologne, Cologne, Germany
  • Höhne, Martin, Department II of Internal Medicine, University hospital of Cologne, Cologne, Germany
  • Lucas, Christina, Syft Technologies GmbH, Darmstadt, Germany
  • Brodesser, Susanne, Exzellenzcluster CECAD in der Universitat zu Koln, Koln, Nordrhein-Westfalen, Germany
  • Lackmann, Jan-Wilm, Exzellenzcluster CECAD in der Universitat zu Koln, Koln, Nordrhein-Westfalen, Germany
  • Kiefer, Katharina, Exzellenzcluster CECAD in der Universitat zu Koln, Koln, Nordrhein-Westfalen, Germany
  • Koehler, Felix C., Department II of Internal Medicine, University hospital of Cologne, Cologne, Germany
  • Kubacki, Torsten, Department II of Internal Medicine, University hospital of Cologne, Cologne, Germany
  • Grundmann, Franziska, Department II of Internal Medicine, University hospital of Cologne, Cologne, Germany
  • Benzing, Thomas, Department II of Internal Medicine, University hospital of Cologne, Cologne, Germany
  • Schermer, Bernhard, Department II of Internal Medicine, University hospital of Cologne, Cologne, Germany
  • Burst, Volker Rolf, Department II of Internal Medicine, University hospital of Cologne, Cologne, Germany
  • Mueller, Roman-Ulrich, Department II of Internal Medicine, University hospital of Cologne, Cologne, Germany
Background

In clinical practice, targeted measures for the treatment of acute kidney injury (AKI) are lacking. In mouse models, AKI by ischemia-reperfusion injury (IRI) can be reduced effectively through preconditioning protocols using hypoxia (HP) or caloric restriction (CR). In previous transcriptome analyses of murine kidneys after HP or CR, we identified Kynu as a common downstream target. The kynureninase encoded by Kynu is one of the key enzymes in tryptophan metabolism and the aim of this work was to further characterize the role of KYNU in the protection of AKI.

Methods

CRISPR-cas9 based non-homologous end joining (NHEJ) resulted in a KYNU-deficiency in C57Bl6 mice. This was followed by basal (e.g. biometry, kidney function) and special (e.g. kidney function 24h after renal IRI with or without HP/CR) phenotyping of the KYNU-deficient (KYNUnull) mice in comparison to wildtype littermates (KYNUwt ). The changes in the murine transcriptome, proteome and tryptophan metabolism mediated by HP and CR were then investigated before and after renal IRI. Finally, confirmatory analyses of the CR-mediated changes in the tryptophan metabolism of human blood samples were carried out.

Results

NHEJ resulted in a nonsense mutation in Kynu exon 2 and various protein analyses (e.g. Western blot and immunohistochemistry) confirmed the KYNU-deficiency. In the basal phenotyping and 24 h after IRI, KYNUnull mice showed no differences from KYNUwt mice. However, the protection mediated by HP was no longer detectable in KYNUnull mice and after CR the KYNUnull mice showed significantly worse AKI than the KYNUwt littermates. Analyses of the transcriptome, proteome and tryptophan metabolism showed that KYNU is necessary for CR-mediated maintenance of nicotinamide adenine dinucleotide levels (NAD+) by inducing de novo NAD+ synthesis. The changes in de novo NAD+ synthesis identified in murine blood and induced by CR can also be recapitulated in human blood samples.

Conclusion

The CR-mediated induction of Kynu results from an increased activity of the de novo branch of NAD+ synthesis, which can also be recapitulated in humans. This finding offers new options for targeted therapeutic measures for the treatment of AKI.