Tissue Metabolic Profiling Shows That Saccharopine Accumulates During Renal Ischemic-reperfusion Injury, While Kynurenine and Itaconate Accumulate in Renal Allograft Rejection

Overview

Journal Metabolomics

Publisher Springer

Specialty Endocrinology

Date 2020 May 6

PMID 32367163

Citations 7

Authors

Ulf H Beier

Erum A Hartung

Seth Concors

Paul T Hernandez

Zhonglin Wang

Caroline Perry

Joseph A Baur

Michelle R Denburg

Wayne W Hancock

Terence P Gade

Matthew H Levine

Affiliations

Soon will be listed here.

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.

Citing Articles

Immune-response gene 1 deficiency aggravates inflammation-triggered cardiac dysfunction by inducing M1 macrophage polarization and aggravating Ly6C monocyte recruitment.

Shen S, Li J, Wei Z, Liu Y, Kang L, Gu R Biol Direct. 2024; 19(1):86.

PMID: 39350193 PMC: 11441264. DOI: 10.1186/s13062-024-00521-x.

Gut Microbiota Combined with Metabolomics Reveal the Mechanisms of Sika Deer Antler Protein on Cisplatin-Induced Hepatorenal Injury in Mice.

Wang L, Li L, Wang Z, Zhang P, Zhang J Molecules. 2023; 28(18).

PMID: 37764239 PMC: 10537820. DOI: 10.3390/molecules28186463.

A Review of Current and Emerging Trends in Donor Graft-Quality Assessment Techniques.

Warmuzinska N, Luczykowski K, Bojko B J Clin Med. 2022; 11(3).

PMID: 35159939 PMC: 8836899. DOI: 10.3390/jcm11030487.

Itaconate as an inflammatory mediator and therapeutic target in cardiovascular medicine.

Diotallevi M, Ayaz F, Nicol T, Crabtree M Biochem Soc Trans. 2021; 49(5):2189-2198.

PMID: 34665229 PMC: 8589439. DOI: 10.1042/BST20210269.

Preclinical models versus clinical renal ischemia reperfusion injury: A systematic review based on metabolic signatures.

Lerink L, de Kok M, Mulvey J, Le Devedec S, Markovski A, Wust R Am J Transplant. 2021; 22(2):344-370.

PMID: 34657378 PMC: 9298342. DOI: 10.1111/ajt.16868.

References

Zhou J, Wang X, Wang M, Chang Y, Zhang F, Ban Z . The lysine catabolite saccharopine impairs development by disrupting mitochondrial homeostasis. J Cell Biol. 2018; 218(2):580-597. PMC: 6363459. DOI: 10.1083/jcb.201807204. View

Chouchani E, Pell V, Gaude E, Aksentijevic D, Sundier S, Robb E . Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS. Nature. 2014; 515(7527):431-435. PMC: 4255242. DOI: 10.1038/nature13909. View

Levine M, Wang Z, Bhatti T, Wang Y, Aufhauser D, McNeal S . Class-specific histone/protein deacetylase inhibition protects against renal ischemia reperfusion injury and fibrosis formation. Am J Transplant. 2015; 15(4):965-73. PMC: 5493154. DOI: 10.1111/ajt.13106. View

Danhauser K, Sauer S, Haack T, Wieland T, Staufner C, Graf E . DHTKD1 mutations cause 2-aminoadipic and 2-oxoadipic aciduria. Am J Hum Genet. 2012; 91(6):1082-7. PMC: 3516599. DOI: 10.1016/j.ajhg.2012.10.006. View

Mills E, Ryan D, Prag H, Dikovskaya D, Menon D, Zaslona Z . Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1. Nature. 2018; 556(7699):113-117. PMC: 6047741. DOI: 10.1038/nature25986. View

Shen H, Campanello G, Flicker D, Grabarek Z, Hu J, Luo C . The Human Knockout Gene CLYBL Connects Itaconate to Vitamin B. Cell. 2017; 171(4):771-782.e11. PMC: 5827971. DOI: 10.1016/j.cell.2017.09.051. View

Mezrich J, Fechner J, Zhang X, Johnson B, Burlingham W, Bradfield C . An interaction between kynurenine and the aryl hydrocarbon receptor can generate regulatory T cells. J Immunol. 2010; 185(6):3190-8. PMC: 2952546. DOI: 10.4049/jimmunol.0903670. View

Christians U, Klawitter J, Klawitter J . Biomarkers in Transplantation--Proteomics and Metabolomics. Ther Drug Monit. 2015; 38 Suppl 1:S70-4. PMC: 4769975. DOI: 10.1097/FTD.0000000000000243. View

Fallarino F, Grohmann U, Vacca C, Bianchi R, Orabona C, Spreca A . T cell apoptosis by tryptophan catabolism. Cell Death Differ. 2002; 9(10):1069-77. DOI: 10.1038/sj.cdd.4401073. View

10.

Tran M, Zsengeller Z, Berg A, Khankin E, Bhasin M, Kim W . PGC1α drives NAD biosynthesis linking oxidative metabolism to renal protection. Nature. 2016; 531(7595):528-32. PMC: 4909121. DOI: 10.1038/nature17184. View

11.

Addi T, Dou L, Burtey S . Tryptophan-Derived Uremic Toxins and Thrombosis in Chronic Kidney Disease. Toxins (Basel). 2018; 10(10). PMC: 6215213. DOI: 10.3390/toxins10100412. View

12.

Malek M, Nematbakhsh M . Renal ischemia/reperfusion injury; from pathophysiology to treatment. J Renal Inj Prev. 2015; 4(2):20-7. PMC: 4459724. DOI: 10.12861/jrip.2015.06. View

13.

Quintana F, Basso A, Iglesias A, Korn T, Farez M, Bettelli E . Control of T(reg) and T(H)17 cell differentiation by the aryl hydrocarbon receptor. Nature. 2008; 453(7191):65-71. DOI: 10.1038/nature06880. View

14.

Fox B, Gil H, Kirkbride-Romeo L, Bagchi R, Wennersten S, Haefner K . Metabolomics assessment reveals oxidative stress and altered energy production in the heart after ischemic acute kidney injury in mice. Kidney Int. 2019; 95(3):590-610. PMC: 6564679. DOI: 10.1016/j.kint.2018.10.020. View

15.

Leandro J, Houten S . Saccharopine, a lysine degradation intermediate, is a mitochondrial toxin. J Cell Biol. 2019; 218(2):391-392. PMC: 6363453. DOI: 10.1083/jcb.201901033. View

16.

Lampropoulou V, Sergushichev A, Bambouskova M, Nair S, Vincent E, Loginicheva E . Itaconate Links Inhibition of Succinate Dehydrogenase with Macrophage Metabolic Remodeling and Regulation of Inflammation. Cell Metab. 2016; 24(1):158-66. PMC: 5108454. DOI: 10.1016/j.cmet.2016.06.004. View

17.

McMahon M, Itoh K, Yamamoto M, Hayes J . Keap1-dependent proteasomal degradation of transcription factor Nrf2 contributes to the negative regulation of antioxidant response element-driven gene expression. J Biol Chem. 2003; 278(24):21592-600. DOI: 10.1074/jbc.M300931200. View

18.

Levine M, Wang Z, Xiao H, Jiao J, Wang L, Bhatti T . Targeting Sirtuin-1 prolongs murine renal allograft survival and function. Kidney Int. 2016; 89(5):1016-1026. PMC: 4834143. DOI: 10.1016/j.kint.2015.12.051. View

19.

Perico L, Wyatt C, Benigni A . A new BEACON of hope for the treatment of inflammation? The endogenous metabolite itaconate as an alternative activator of the KEAP1-Nrf2 system. Kidney Int. 2018; 94(4):646-649. DOI: 10.1016/j.kint.2018.07.018. View