Metabolic and Immune Mechanisms of L-Lysine in Salt-Sensitive Hypertension

Salt-sensitive hypertension (SS-HTN) is a major driver of chronic kidney disease (CKD). High salt (HS) in vulnerable individuals raises blood pressure (BP) and promotes renal injury, albuminuria, and inflammation. Mitochondrial dysfunction and impaired fatty acid oxidation (FAO) further exacerbate disease progression. Although current therapies lower BP, they do not target the underlying immune-metabolic drivers of SS-HTN progression. L-lysine is an essential amino acid required for various physiological functions. Prior studies have shown that plasma lysine levels are significantly reduced in young hypertensive men and identified it as a central node within metabolic correlation networks. Our laboratory previously reported that renal lysine levels are markedly depleted in the Dahl SS rat model of SS-HTN, and that dietary L-lysine supplementation attenuates the progression of hypertension. However, this treatment was given simultaneously with the progression of hypertension, which cannot be translated into the direct therapeutic potential of the amino acid. Since HS disrupts amino acid metabolism in SS-HTN, we hypothesize that therapeutic dietary L-lysine supplementation mitigates SS-HTN by reducing proximal tubular stress and reprogramming immunometabolic pathways, including a shift in FAO towards peroxisomal processes and attenuation of inflammatory signaling. Male (N=19) and female (N=18) Dahl salt-sensitive rats received a HS diet, followed by therapeutic L-lysine supplementation in drinking water. Blood pressure was continuously monitored via radiotelemetry. Urine was collected at key time points to measure kidney electrolytes, creatinine clearance, and albuminuria. At the study endpoint, kidneys, liver, and plasma were collected for histology, omics analyses, and flow cytometry. Ingenuity Pathway Analysis was used to integrate metabolomics, lipidomics, and proteomics datasets to identify key pathways altered by L-lysine treatment. Therapeutic L-lysine supplementation significantly reduced BP and tubular injury without compromising renal function. IPA highlighted acyl-CoA oxidase (ACOX1) as an upstream regulator of lysine-mediated renoprotection (p-value < 4E-03). Consistent with this, we observed significant upregulation of peroxisomal β-oxidation enzymes ACOX2, ACAA1B, HSD17B4, and ACOT8 (log2 FC 1.03, 0.24, 0.19, 0.46, respectively, p-value < 0.05) indicating a metabolic shift away from impaired mitochondrial FAO. This shift reduced oxidative stress and lipid droplet accumulation. Kidney markers RIG-1 and MYD88 (log2 FC 0.22, 0.19, respectively, p-value < 0.05) shifted towards a reparative anti-inflammatory phenotype. Future studies will examine how lysine-mediated peroxisomal FAO changes immune cell recruitment and activation. These will include spatial mapping and flow cytometry to assess T cell and macrophage infiltration and characterization. Overall, L-lysine supplementation improves renal function and reduces injury while redirecting FAO to alleviate mitochondrial dysfunction and modulating inflammatory signaling. These findings support L-lysine as a promising metabolic-immune therapeutic strategy for SS-HTN. Disclosure of Funding Sources: Department of Veteran Affairs supports this work grant I01 BX004024 (to A.S.) and American Heart Association 25POST1375066 (to LVD). This abstract was presented at the American Physiology Summit 2026 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.