Abstract
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 language | English (US) |
|---|---|
| Article number | 109547 |
| Journal | Cell reports |
| Volume | 36 |
| Issue number | 7 |
| DOIs | |
| State | Published - Aug 17 2021 |
Funding
This work was supported by National Institutes of Health (NIH) grants P20 GM104936 (P.P.K.), R01DK115850 (P.P.K.), R35GM119528 (R.L.), T32DK071496 (R. Torosyan). Metabolomics services were performed by the Metabolomics Core Facility at Robert H. Lurie Comprehensive Cancer Center of Northwestern University. We acknowledge the Northwestern University George M. O'Brien Kidney Research Core Center (NU GoKidney), an NIH/NIDDK-funded program (P30 DK114857), for their core services and support. We thank Breeanna Mintmier (West Virginia University) for performing LC/UV-based quantification of serum kynurenine. The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. P.P.K. and R. Torosyan conceived the study; S.H. R. Torosyan, P.V.B. and P.P.K. designed the experiments; S.H. R. Torosyan, R. Tiwari, S.A. M.P.S. G.R. M.K. B.G. E.W.K. and P.P.K. performed experiments; S.H. R. Torosyan, P.V.B. R. Tiwari, S.A. M.P.S. G.R. M.K. B.G. A.T. S.B. E.W.K. R.L. P.G. N.S.D. and P.P.K. analyzed and interpreted data; M.W.C. developed and optimized the quantitative LC/MS assay for measurement of kynurenine and tryptophan; E.W.K. and R.L. developed and optimized the LC/UV-based assay for quantification of kynurenine; P.G. developed and optimized the HPLC-MS/MS assay for measurement of KP metabolites; P.P.K. wrote the manuscript; and all authors approved and commented on the manuscript. The authors declare no competing interests. This work was supported by National Institutes of Health (NIH) grants P20 GM104936 (P.P.K.), R01DK115850 (P.P.K.), R35GM119528 (R.L.), T32DK071496 (R. Torosyan). Metabolomics services were performed by the Metabolomics Core Facility at Robert H. Lurie Comprehensive Cancer Center of Northwestern University. We acknowledge the Northwestern University George M. O’Brien Kidney Research Core Center (NU GoKidney), an NIH / NIDDK -funded program ( P30 DK114857 ), for their core services and support. We thank Breeanna Mintmier (West Virginia University) for performing LC/UV-based quantification of serum kynurenine. The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Keywords
- IDO1
- NAD
- PHDs
- hypoxia
- ischemia-reperfusion
- kidney
- kynurenic acid
- kynurenine
- preconditioning
ASJC Scopus subject areas
- General Biochemistry, Genetics and Molecular Biology