Lysine metabolism conveys kidney protection in hypertension

Abstract Hypertension and kidney disease, two related, common, and severe disease entities, have been repeatedly associated with genomic variants and metabolic alterations of lysine metabolism. Here, we developed a stable isotope labeling strategy compatible with untargeted metabolomics acquisition to investigate the physiology and molecular spectrum of lysine’s metabolic fate in vivo. Mice received 13C6 labeled lysine through the diet over two months to track more than 100 lysine metabolites across various organs and body fluids. Lysine reacts rapidly with molecules of the central carbon metabolism, as opposed to slow or incorporation into proteins and metabolization into acylcarnitines. The kidney rapidly forms these lysine conjugates and lysine metabolism is decreased in early stages of hypertension. Lysine administration completely diminished the development of salt-sensitive hypertension and kidney injury in the Dahl salt-sensitive rat model. Administration of lysine leads to diuresis, acceleration of 13C6 lysine conjugate formation, and inhibition of albumin uptake, thereby protecting from nephron injury and metabolic stress. Lysine conjugates with malonyl-CoA to form a novel metabolite Ne-malonyl-lysine to inhibit fatty acid synthesis. Formation of Ne-malonyl-Lysine, and acetyl-Lysine during lysine treatment depletes malonyl-CoA and acetyl-CoA, respectively, a process that occurs at the expense of protein malonylation and acetylation. A significant fraction of lysine molecules was metabolized in the kidney and excreted as fructoselysine and saccharopine, via the urine, leading to an overall depletion of central carbon metabolites from the organism. A ketogenic diet also ameliorated hypertension, yet to a lower extent, and increased several lysine conjugates, including Ne-malonyl-lysine. In conclusion, isotope tracing of orally administered lysine illuminated lysine metabolism, and L-lysine protects the kidneys in metabolically defined subtypes of kidney disease.