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Accelerated lysine metabolism conveys kidney protection in salt-sensitive hypertension

Author

Listed:
  • Markus M. Rinschen

    (Scripps Research
    Aarhus University
    University Hospital Hamburg Eppendorf
    AIAS, Aarhus Institute of Advanced Studies (AIAS), Aarhus University)

  • Oleg Palygin

    (Medical University of South Carolina)

  • Ashraf El-Meanawy

    (Medical College of Wisconsin)

  • Xavier Domingo-Almenara

    (Scripps Research
    Omics Sciences Unit, EURECAT, Technology Centre of Catalonia)

  • Amelia Palermo

    (Scripps Research
    David Geffen School of Medicine, University of California)

  • Lashodya V. Dissanayake

    (University of South Florida
    Medical College of Wisconsin)

  • Daria Golosova

    (Medical College of Wisconsin)

  • Michael A. Schafroth

    (Scripps Research)

  • Carlos Guijas

    (Scripps Research)

  • Fatih Demir

    (Aarhus University)

  • Johannes Jaegers

    (Aarhus University)

  • Megan L. Gliozzi

    (University of Pittsburgh School of Medicine)

  • Jingchuan Xue

    (Scripps Research)

  • Martin Hoehne

    (Center for Molecular Medicine Cologne
    Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases
    University Hospital of Cologne)

  • Thomas Benzing

    (Center for Molecular Medicine Cologne
    Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases
    University Hospital of Cologne)

  • Bernard P. Kok

    (Scripps Research)

  • Enrique Saez

    (Scripps Research)

  • Markus Bleich

    (University Kiel)

  • Nina Himmerkus

    (University Kiel)

  • Ora A. Weisz

    (University of Pittsburgh School of Medicine)

  • Benjamin F. Cravatt

    (Scripps Research)

  • Marcus Krüger

    (Center for Molecular Medicine Cologne
    Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases)

  • H. Paul Benton

    (Scripps Research)

  • Gary Siuzdak

    (Scripps Research)

  • Alexander Staruschenko

    (University of South Florida
    Medical College of Wisconsin
    James A. Haley Veterans’ Hospital
    University of South Florida)

Abstract

Hypertension and kidney disease have been repeatedly associated with genomic variants and alterations of lysine metabolism. Here, we combined stable isotope labeling with untargeted metabolomics to investigate lysine’s metabolic fate in vivo. Dietary 13C6 labeled lysine was tracked to lysine metabolites across various organs. Globally, lysine reacts rapidly with molecules of the central carbon metabolism, but incorporates slowly into proteins and acylcarnitines. Lysine metabolism is accelerated in a rat model of hypertension and kidney damage, chiefly through N-alpha-mediated degradation. Lysine administration diminished development of hypertension and kidney injury. Protective mechanisms include diuresis, further acceleration of lysine conjugate formation, and inhibition of tubular albumin uptake. Lysine also conjugates with malonyl-CoA to form a novel metabolite Nε-malonyl-lysine to deplete malonyl-CoA from fatty acid synthesis. Through conjugate formation and excretion as fructoselysine, saccharopine, and Nε-acetyllysine, lysine lead to depletion of central carbon metabolites from the organism and kidney. Consistently, lysine administration to patients at risk for hypertension and kidney disease inhibited tubular albumin uptake, increased lysine conjugate formation, and reduced tricarboxylic acid (TCA) cycle metabolites, compared to kidney-healthy volunteers. In conclusion, lysine isotope tracing mapped an accelerated metabolism in hypertension, and lysine administration could protect kidneys in hypertensive kidney disease.

Suggested Citation

  • Markus M. Rinschen & Oleg Palygin & Ashraf El-Meanawy & Xavier Domingo-Almenara & Amelia Palermo & Lashodya V. Dissanayake & Daria Golosova & Michael A. Schafroth & Carlos Guijas & Fatih Demir & Johan, 2022. "Accelerated lysine metabolism conveys kidney protection in salt-sensitive hypertension," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31670-0
    DOI: 10.1038/s41467-022-31670-0
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