Accelerated lysine metabolism conveys kidney protection in salt-sensitive hypertension
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Accelerated lysine metabolism conveys kidney protection in salt-sensitive hypertension. / Rinschen, Markus M; Palygin, Oleg; El-Meanawy, Ashraf; Domingo-Almenara, Xavier; Palermo, Amelia; Dissanayake, Lashodya V; Golosova, Daria; Schafroth, Michael A; Guijas, Carlos; Demir, Fatih; Jaegers, Johannes; Gliozzi, Megan L; Xue, Jingchuan; Hoehne, Martin; Benzing, Thomas; Kok, Bernard P; Saez, Enrique; Bleich, Markus; Himmerkus, Nina; Weisz, Ora A; Cravatt, Benjamin F; Krüger, Marcus; Benton, H Paul; Siuzdak, Gary; Staruschenko, Alexander.
in: NAT COMMUN, Jahrgang 13, Nr. 1, 4099, 14.07.2022.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Accelerated lysine metabolism conveys kidney protection in salt-sensitive hypertension
AU - Rinschen, Markus M
AU - Palygin, Oleg
AU - El-Meanawy, Ashraf
AU - Domingo-Almenara, Xavier
AU - Palermo, Amelia
AU - Dissanayake, Lashodya V
AU - Golosova, Daria
AU - Schafroth, Michael A
AU - Guijas, Carlos
AU - Demir, Fatih
AU - Jaegers, Johannes
AU - Gliozzi, Megan L
AU - Xue, Jingchuan
AU - Hoehne, Martin
AU - Benzing, Thomas
AU - Kok, Bernard P
AU - Saez, Enrique
AU - Bleich, Markus
AU - Himmerkus, Nina
AU - Weisz, Ora A
AU - Cravatt, Benjamin F
AU - Krüger, Marcus
AU - Benton, H Paul
AU - Siuzdak, Gary
AU - Staruschenko, Alexander
N1 - © 2022. The Author(s).
PY - 2022/7/14
Y1 - 2022/7/14
N2 - 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.
AB - 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.
KW - Albumins/metabolism
KW - Animals
KW - Carbon/metabolism
KW - Humans
KW - Hypertension/metabolism
KW - Kidney/metabolism
KW - Lysine/metabolism
KW - Malonyl Coenzyme A/metabolism
KW - Rats
U2 - 10.1038/s41467-022-31670-0
DO - 10.1038/s41467-022-31670-0
M3 - SCORING: Journal article
C2 - 35835746
VL - 13
JO - NAT COMMUN
JF - NAT COMMUN
SN - 2041-1723
IS - 1
M1 - 4099
ER -