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Tissue metabolic profiling shows that saccharopine accumulates during renal ischemic-reperfusion injury, while kynurenine and itaconate accumulate in renal allograft rejection

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Abstract

To examine metabolic differences between renal allograft acute cellular rejection (ACR) and ischemic-reperfusion injury (IRI), we transplanted MHC-mismatched kidneys and induced 28 min warm-IRI, and collected the ACR and IRI kidneys as well as their respective native and collateral control kidneys. We extracted metabolites from the kidney tissues and found the lysine catabolite saccharopine 12.5-fold enriched in IRI kidneys, as well as the immunometabolites itaconate and kynurenine in ACR kidneys. Saccharopine accumulation is known to be toxic to mitochondria and may contribute to IRI pathophysiology, while itaconate and kynurenine may be reflective of counterregulatory responses to immune activation in ACR.

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References

  • Addi, T., Dou, L., & Burtey, S. (2018). Tryptophan-derived uremic toxins and thrombosis in chronic kidney disease. Toxins,10(10), 412.

    Article  CAS  Google Scholar 

  • Beier, U. H., Cully, M. D., Siska, P. J., Singer, K., Jiao, J., TeSlaa, T., et al. (2019). Fatty acid depletion is a reversible cause of kynurenine induced T cell apoptosis. The Journal of Immunology,202(1 Supplement), 137.1.

    Google Scholar 

  • Chouchani, E. T., Pell, V. R., Gaude, E., Aksentijevic, D., Sundier, S. Y., Robb, E. L., et al. (2014). Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS. Nature,515(7527), 431–435.

    Article  CAS  Google Scholar 

  • Christians, U., Klawitter, J., & Klawitter, J. (2016). Biomarkers in transplantation-proteomics and metabolomics. Therapeutic Drug Monitoring,38(Suppl 1), S70–S74.

    Article  CAS  Google Scholar 

  • Danhauser, K., Sauer, S. W., Haack, T. B., Wieland, T., Staufner, C., Graf, E., et al. (2012). DHTKD1 mutations cause 2-aminoadipic and 2-oxoadipic aciduria. American Journal of Human Genetics,91(6), 1082–1087.

    Article  CAS  Google Scholar 

  • Fallarino, F., Grohmann, U., Vacca, C., Bianchi, R., Orabona, C., Spreca, A., et al. (2002). T cell apoptosis by tryptophan catabolism. Cell Death and Differentiation,9(10), 1069–1077.

    Article  CAS  Google Scholar 

  • Fox, B. M., Gil, H. W., Kirkbride-Romeo, L., Bagchi, R. A., Wennersten, S. A., Haefner, K. R., et al. (2019). Metabolomics assessment reveals oxidative stress and altered energy production in the heart after ischemic acute kidney injury in mice. Kidney International,95(3), 590–610.

    Article  CAS  Google Scholar 

  • Lampropoulou, V., Sergushichev, A., Bambouskova, M., Nair, S., Vincent, E. E., Loginicheva, E., et al. (2016). Itaconate links inhibition of succinate dehydrogenase with macrophage metabolic remodeling and regulation of inflammation. Cell Metabolism,24(1), 158–166.

    Article  CAS  Google Scholar 

  • Leandro, J., & Houten, S. M. (2019). Saccharopine, a lysine degradation intermediate, is a mitochondrial toxin. Journal of Cell Biology,218(2), 391–392.

    Article  CAS  Google Scholar 

  • Levine, M. H., Wang, Z., Bhatti, T. R., Wang, Y., Aufhauser, D. D., McNeal, S., et al. (2015). Class-specific histone/protein deacetylase inhibition protects against renal ischemia reperfusion injury and fibrosis formation. American Journal of Transplantation,15(4), 965–973.

    Article  CAS  Google Scholar 

  • Levine, M. H., Wang, Z., Xiao, H., Jiao, J., Wang, L., Bhatti, T. R., et al. (2016). Targeting Sirtuin-1 prolongs murine renal allograft survival and function. Kidney International,89(5), 1016–1026.

    Article  CAS  Google Scholar 

  • Malek, M., & Nematbakhsh, M. (2015). Renal ischemia/reperfusion injury; from pathophysiology to treatment. J Renal Inj Prev,4(2), 20–27.

    CAS  PubMed  PubMed Central  Google Scholar 

  • McMahon, M., Itoh, K., Yamamoto, M., & Hayes, J. D. (2003). Keap1-dependent proteasomal degradation of transcription factor Nrf2 contributes to the negative regulation of antioxidant response element-driven gene expression. Journal of Biological Chemistry,278(24), 21592–21600.

    Article  CAS  Google Scholar 

  • Mezrich, J. D., Fechner, J. H., Zhang, X., Johnson, B. P., Burlingham, W. J., & Bradfield, C. A. (2010). An interaction between kynurenine and the aryl hydrocarbon receptor can generate regulatory T cells. The Journal of Immunology,185(6), 3190–3198.

    Article  CAS  Google Scholar 

  • Mills, E. L., Ryan, D. G., Prag, H. A., Dikovskaya, D., Menon, D., Zaslona, Z., et al. (2018). Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1. Nature,556(7699), 113–117.

    Article  CAS  Google Scholar 

  • Perico, L., Wyatt, C. M., & Benigni, A. (2018). A new BEACON of hope for the treatment of inflammation? The endogenous metabolite itaconate as an alternative activator of the KEAP1-Nrf2 system. Kidney International,94(4), 646–649.

    Article  Google Scholar 

  • Quintana, F. J., Basso, A. S., Iglesias, A. H., Korn, T., Farez, M. F., Bettelli, E., et al. (2008). Control of T(reg) and T(H)17 cell differentiation by the aryl hydrocarbon receptor. Nature,453(7191), 65–71.

    Article  CAS  Google Scholar 

  • Shen, H., Campanello, G. C., Flicker, D., Grabarek, Z., Hu, J., Luo, C., et al. (2017). The human knockout gene CLYBL connects itaconate to vitamin B12. Cell,171(4), 771–782.e11.

    Article  CAS  Google Scholar 

  • Tran, M. T., Zsengeller, Z. K., Berg, A. H., Khankin, E. V., Bhasin, M. K., Kim, W., et al. (2016). PGC1alpha drives NAD biosynthesis linking oxidative metabolism to renal protection. Nature,531(7595), 528–532.

    Article  CAS  Google Scholar 

  • Zhou, J., Wang, X., Wang, M., Chang, Y., Zhang, F., Ban, Z., et al. (2019). The lysine catabolite saccharopine impairs development by disrupting mitochondrial homeostasis. Journal of Cell Biology,218(2), 580–597.

    Article  CAS  Google Scholar 

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Funding

This study was funded by the University of Pennsylvania (Penn) Institute for Translational Medicine and Therapeutics (to EAH, TPG, MHL, UHB); Laffey McHugh Foundation & American Society of Nephrology (to UHB); National Institutes of Health (Grant Nos. DK109203 to EAH, AG043483 to JAB, OD021391 to TPG, DK106243 to MHL, and UL1TR001878 to Penn).

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Author notes

  1. Ulf H. Beier and Erum A. Hartung have contributed equally.

Authors and Affiliations

  1. Division of Nephrology, Department of Pediatrics, Children’s Hospital of Philadelphia and Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA

    Ulf H. Beier, Erum A. Hartung & Michelle R. Denburg

  2. Department of Transplant Surgery, Penn Transplant Institute, Perelman School of Medicine, Children’s Hospital of Philadelphia and University of Pennsylvania, 3400 Spruce Street, 2 Ravdin Courtyard, Philadelphia, PA, 19104, USA

    Seth Concors, Paul T. Hernandez, Zhonglin Wang & Matthew H. Levine

  3. Department of Physiology and Institute of Diabetes, Obesity, and Metabolism, University of Pennsylvania, Philadelphia, PA, 19104, USA

    Caroline Perry & Joseph A. Baur

  4. Division of Transplant Immunology, Department of Pathology and Laboratory Medicine, Biesecker Center for Pediatric Liver Disease, Children’s Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA, 19104, USA

    Wayne W. Hancock

  5. Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA

    Terence P. Gade

  6. Department of Cancer Biology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA

    Terence P. Gade

Authors
  1. Ulf H. Beier
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  2. Erum A. Hartung
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  3. Seth Concors
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  4. Paul T. Hernandez
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  5. Zhonglin Wang
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  6. Caroline Perry
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  7. Joseph A. Baur
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  8. Michelle R. Denburg
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  9. Wayne W. Hancock
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  10. Terence P. Gade
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  11. Matthew H. Levine
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Contributions

EAH, MHL, UHB, TPG, MRD: Research idea and study design; SC, PTH, ZW, CP: Data acquisition; UHB, EAH, TPG, WWH, MHL, CP, JAB: data analysis/interpretation; UHB, EAH, MRD: statistical analysis; UHB: writing manuscript; EAH, PTH, SC, WWH, MHL, TPG, MRD, CP, JAB: editing manuscript.

Corresponding author

Correspondence to Matthew H. Levine.

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The authors declare no conflict of interest.

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

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No humans were involved in the study.

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Beier, U.H., Hartung, E.A., Concors, S. et al. Tissue metabolic profiling shows that saccharopine accumulates during renal ischemic-reperfusion injury, while kynurenine and itaconate accumulate in renal allograft rejection. Metabolomics 16, 65 (2020). https://doi.org/10.1007/s11306-020-01682-2

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  • DOI: https://doi.org/10.1007/s11306-020-01682-2

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