Therapeutic Lysine Supplementation Attenuates Salt-Sensitive Hypertension Through Potential Modulation of Fatty Acid Metabolism

Salt-sensitive (SS) hypertension (HTN) affects about 50% of hypertensive individuals, posing challenges for diagnosis and treatment. Dahl SS rats, a model of SS HTN, exhibit increased blood pressure and worsening albuminuria, leading to significant kidney damage on a high salt (HS) diet. Our previous research showed that HS feeding depletes amino acids like lysine in tubules and alters lipid and energy metabolism in glomeruli, inhibiting mTOR signaling in Dahl SS rats. Supplementing rats with lysine in water alongside a HS diet reduced HTN and kidney damage by inhibiting albumin uptake, promoting diuresis, and enhancing lysine metabolism for protective effects. The current study examines whether lysine supplementation can serve as a therapeutic approach to reducing established hypertension. We used male (N=17) Dahl SS rats implanted with radiotelemetry and fed them a HS diet for 10 days. When rats developed mean arterial pressure of >140 mmHg they were randomly assigned to a treatment (lysine chloride; 17mg/ml in drinking water) or vehicle groups, and the HS diet was given for another 11 days. The kidney, liver, plasma, and urine at the endpoint were subjected to proteomics and targeted metabolomics for amino acids. We hypothesized that lysine administration would be beneficial in controlling established HTN by metabolic alterations. Lysine-treated rats had a significant attenuation of the MAP (145± 4 vs. 179± 6mmHg, p=0.0004) compared to the control group. Lysine levels increased in the treatment group within the kidney, plasma, and urine, while alpha-aminoadipic acid, a lysine degradation product, also rose in the kidney and plasma. Further analysis of the proteomic data (lysine-treated group vs. vehicle) through Ingenuity Pathway Analysis revealed that the main changes in all tissue types were related to fatty acid (FA) metabolism. Kidney proteome changes suggested acyl-CoA oxidase 1 (ACOX1), the first enzyme necessary for FA β-oxidation as an upstream regulator (p-value of overlap 4.22E-03) based on the upregulation of Oat, Rgn, and Akr1c12 genes. The upregulation of Acox2, Scd1, Kat2b, and Cyp2c55 and the downregulation of Pomc, Slc22a1, and Lrp10 in the kidney also indicate changes in FA metabolism. In the liver, a causal network consisting of master regulators FAF2 and RAS, with activation z-scores of 2.3 and 2.1, respectively, was proposed to activate the mTOR signaling pathway. Alox15, a key enzyme in metabolizing polyunsaturated FA, was also increased in urine. Finally, in plasma, tripeptide Arg-Gly-Asp was suggested as a master regulator (activation z score 2.4) to activate AKT and P38 MAPK families. Our findings indicate that lysine supplementation can effectively reduce SS HTN, potentially by altering FA metabolism. This work is supported by Department of Veteran Affairs grant I01 BX004024 (to A.S.) and ASN Ben J. Lipps Research Fellowship (to LVD). This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.