Faculty Collaboration Database

Accelerated lysine metabolism conveys kidney protection in salt-sensitive hypertension. Nat Commun 2022 Jul 14;13(1):4099

Date

07/15/2022

Pubmed ID

35835746

Pubmed Central ID

PMC9283537

DOI

10.1038/s41467-022-31670-0

Scopus ID

2-s2.0-85134142317 (requires institutional sign-in at Scopus site)   18 Citations

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.

Author List

Rinschen MM, Palygin O, El-Meanawy A, Domingo-Almenara X, Palermo A, Dissanayake LV, Golosova D, Schafroth MA, Guijas C, Demir F, Jaegers J, Gliozzi ML, Xue J, Hoehne M, Benzing T, Kok BP, Saez E, Bleich M, Himmerkus N, Weisz OA, Cravatt BF, Krüger M, Benton HP, Siuzdak G, Staruschenko A

Author

Ashraf El-Meanawy MD, PhD Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Albumins
Animals
Carbon
Disease Models, Animal
Hypertension
Kidney
Lysine
Malonyl Coenzyme A
Rats