Accelerated lysine metabolism conveys kidney protection in salt-sensitive hypertension

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, Johannes Jaegers, Megan L. Gliozzi, Jingchuan Xue, Martin Hoehne, Thomas Benzing, Bernard P. Kok, Enrique Saez, Markus Bleich, Nina Himmerkus, Ora A. Weisz, Benjamin F. Cravatt, Marcus Krüger, H. Paul Benton, Gary Siuzdak () and Alexander Staruschenko ()
Additional contact information
Markus M. Rinschen: Scripps Research
Oleg Palygin: Medical University of South Carolina
Ashraf El-Meanawy: Medical College of Wisconsin
Xavier Domingo-Almenara: Scripps Research
Amelia Palermo: Scripps Research
Lashodya V. Dissanayake: University of South Florida
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
Thomas Benzing: Center for Molecular Medicine 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
H. Paul Benton: Scripps Research
Gary Siuzdak: Scripps Research
Alexander Staruschenko: University of South Florida

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-31670-0

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