Hypoxic preconditioning protects against ischemic kidney injury through the IDO1/kynurenine pathway

Rafael Torosyan, Shengping Huang, Prashant V. Bommi, Ratnakar Tiwari, Si Young An, Michael Schonfeld, Ganeshkumar Rajendran, Matthew A. Kavanaugh, Benjamin Gibbs, Agnieszka D. Truax, Samuel Bohney, M. Wade Calcutt, Evan W. Kerr, Roberta Leonardi, Peng Gao, Navdeep S. Chandel, Pinelopi P. Kapitsinou*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

11 Scopus citations


Prolonged cellular hypoxia leads to energetic failure and death. However, sublethal hypoxia can trigger an adaptive response called hypoxic preconditioning. While prolyl-hydroxylase (PHD) enzymes and hypoxia-inducible factors (HIFs) have been identified as key elements of oxygen-sensing machinery, the mechanisms by which hypoxic preconditioning protects against insults remain unclear. Here, we perform serum metabolomic profiling to assess alterations induced by two potent cytoprotective approaches, hypoxic preconditioning and pharmacologic PHD inhibition. We discover that both approaches increase serum kynurenine levels and enhance kynurenine biotransformation, leading to preservation of NAD+ in the post-ischemic kidney. Furthermore, we show that indoleamine 2,3-dioxygenase 1 (Ido1) deficiency abolishes the systemic increase of kynurenine and the subsequent renoprotection generated by hypoxic preconditioning and PHD inhibition. Importantly, exogenous administration of kynurenine restores the hypoxic preconditioning in the context of Ido1 deficiency. Collectively, our findings demonstrate a critical role of the IDO1-kynurenine axis in mediating hypoxic preconditioning.

Original languageEnglish (US)
Article number109547
JournalCell reports
Issue number7
StatePublished - Aug 17 2021


  • IDO1
  • NAD
  • PHDs
  • hypoxia
  • ischemia-reperfusion
  • kidney
  • kynurenic acid
  • kynurenine
  • preconditioning

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)


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