Rinschen, Markus M., Palygin, Oleg, El-Meanawy, Ashraf, Domingo-Almenara, Xavier ORCID: 0000-0002-0133-6863, Palermo, Amelia, Dissanayake, Lashodya, V, Golosova, Daria ORCID: 0000-0002-9663-9639, Schafroth, Michael A., Guijas, Carlos, Demir, Fatih ORCID: 0000-0002-5744-0205, Jaegers, Johannes, Gliozzi, Megan L., Xue, Jingchuan, Hoehne, Martin, Benzing, Thomas ORCID: 0000-0003-0512-1066, Kok, Bernard P., Saez, Enrique, Bleich, Markus ORCID: 0000-0002-1745-2295, Himmerkus, Nina, Weisz, Ora A., Cravatt, Benjamin F., Krueger, Marcus, Benton, H. Paul, Siuzdak, Gary and Staruschenko, Alexander (2022). Accelerated lysine metabolism conveys kidney protection in salt-sensitive hypertension. Nat. Commun., 13 (1). BERLIN: NATURE PORTFOLIO. ISSN 2041-1723

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Abstract

Kidney metabolism in disease is important but not well understood. Here, using isotope-guided metabolomics, the authors show that lysine's metabolic activity conveys kidney protection in hypertension through accelerated metabolism and physiological effects on tubular function. 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 C-13(6) 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 N epsilon-malonyl-lysine to deplete malonyl-CoA from fatty acid synthesis. Through conjugate formation and excretion as fructoselysine, saccharopine, and N epsilon-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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Rinschen, Markus M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Palygin, OlegUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
El-Meanawy, AshrafUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Domingo-Almenara, XavierUNSPECIFIEDorcid.org/0000-0002-0133-6863UNSPECIFIED
Palermo, AmeliaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dissanayake, Lashodya, VUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Golosova, DariaUNSPECIFIEDorcid.org/0000-0002-9663-9639UNSPECIFIED
Schafroth, Michael A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Guijas, CarlosUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Demir, FatihUNSPECIFIEDorcid.org/0000-0002-5744-0205UNSPECIFIED
Jaegers, JohannesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gliozzi, Megan L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Xue, JingchuanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoehne, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Benzing, ThomasUNSPECIFIEDorcid.org/0000-0003-0512-1066UNSPECIFIED
Kok, Bernard P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Saez, EnriqueUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bleich, MarkusUNSPECIFIEDorcid.org/0000-0002-1745-2295UNSPECIFIED
Himmerkus, NinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Weisz, Ora A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cravatt, Benjamin F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Krueger, MarcusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Benton, H. PaulUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Siuzdak, GaryUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Staruschenko, AlexanderUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-695200
DOI: 10.1038/s41467-022-31670-0
Journal or Publication Title: Nat. Commun.
Volume: 13
Number: 1
Date: 2022
Publisher: NATURE PORTFOLIO
Place of Publication: BERLIN
ISSN: 2041-1723
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
BLOOD-PRESSURE; QUANTITATIVE PROTEOMICS; URINARY METABOLITES; ACID; MODEL; PROTEINURIA; ENDOCYTOSIS; EXPRESSION; SYSTEM; DAMAGEMultiple languages
Multidisciplinary SciencesMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/69520

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