Abstract 042: Therapeutic Administration Of L-lysine Leads To The Attenuation Of Salt-sensitive Hypertension

Abstract

Our previous studies using a multilayered omics approach showed a deficiency of lysine metabolites in Dahl Salt-sensitive (SS) rats fed a high-salt (HS) diet. Consequent studies attempted to rewire these metabolic changes by treating the SS rats with lysine in drinking water while on an HS diet. Rats treated with lysine revealed that the treatment significantly attenuated the development of SS hypertension (HTN) and decreased kidney damage via increased diuresis, accelerated lysine metabolism, and inhibited tubular albumin uptake. Our current study hypothesizes that lysine administration will also be beneficial when blood pressure is already elevated. For this purpose, we used a therapeutic approach where we fed 8-week-old male rats with an HS diet for 10 days (at which point they develop moderate kidney damage (by historic data) and a mean arterial pressure (MAP) of ~140 mmHg, N=13) and consequently put on either L-lysine (17 mg/ml drinking water supplement) or vehicle treatment for 11 more days. MAP was continuously measured using radiotelemetry. At the end of the protocol, the L-lysine-treated group showed a significant decrease in MAP compared to the vehicle group (endpoint 145±5 vs. 176±8 mmHg, N=6-7). Next, using targeted metabolomics, we measured 42 amino acids and their derivatives in the kidney, plasma, and urine at the endpoint of these rats to determine the influence of the treatment on amino acid metabolism. Lysine was upregulated in the treatment group in the kidney, plasma, and urinary excretion compared to the control (log 2 FC & p-value: 0.24, 0.01; 1.22, 3.37E-06; 6.6, 0.04; N=4-5 per group). Lysine degradation product, alpha-Aminoadipic-acid was also increased by 1.56-fold and 1.86-fold in the kidney and plasma, respectively (p-value:0.03 & 0.006). Additionally, 13 other amino acids or derivatives significantly changed in the kidney, plasma, or urine. Our current data suggest that L-lysine administration in hypertensive subjects can have therapeutic effects on the progression and magnitude of SS HTN. As shown by our previous study, it is likely the mechanisms behind this beneficial effect lie in the increased lysine metabolism, which can affect critical downstream metabolic pathways such as the TCA cycle and Fatty Acid metabolism.