Background: While some individuals exhibit salt sensitivity, others demonstrate salt resistance or inverse salt sensitivity—blood pressure reduction during high sodium intake. The molecular mechanisms underlying heterogeneous blood pressure responses to dietary sodium remain poorly understood. Deep proteomics provides a new tool to identify molecular mediators of salt resistance and inverse salt sensitivity Methods: We conducted a randomized crossover trial in 20 normotensive adults comparing 8-day periods of low-sodium (10 mmol/day) versus high-sodium (300 mmol/day) diets. Comprehensive plasma proteomic analysis was performed using SomaLogic's 7k proteomics platform, which measures approximately 7,000 human proteins. The change in proteins between the high- and low-sodium diets was compared with the change in blood pressure. Results: Despite average weight difference of +1.4 kg during high- versus low-sodium intake (p=8.85×10-7), diastolic blood pressure and mean arterial pressure were significantly lower (67.0±7.5 vs 69.7±8.0 mm Hg, p=0.014 for diastolic blood pressure; 82.2±7.6 versus 84.8±8.3 mm Hg, p=0.029 for mean arterial pressure). Among approximately 7,000 proteins analyzed, SVEP1 demonstrated one of the most significant responses to sodium loading, with two independent aptamers (antibody-like DNA molecules) ranking 4th (p= 5.33×10-6) and 8th (p=2.19×10-5) in statistical significance. SVEP1 substantially outranked established sodium-regulatory hormones including renin (23rd) and NT-proBNP (16th). SVEP1 upregulation correlated inversely with blood pressure changes (R= -0.50, p=0.028), and individuals exhibiting inverse salt sensitivity demonstrated 2-fold higher SVEP1 responses. Changes in SVEP1 correlated strongly with changes in NT-ProBNP (R= 0.80, p<0.001). Reactome analysis revealed coordinated extracellular matrix remodeling as the dominant biological response to sodium loading. Conclusions: SVEP1 emerges as a primary molecular correlate of blood pressure responses to dietary sodium, likely through a volume- or stretch-mediated stimulus. Given SVEP1's established functions in vascular smooth muscle relaxation and lymphangiogenesis, these findings suggest novel pathways mediating cardiovascular adaptation to sodium challenges and potential biomarkers for identifying salt-sensitive versus salt-resistant individuals.

The authors have declared no competing interest.

NCT04168073

This work was supported by the National Institutes of Health (NHLBI) K23 award HL128909. We acknowledge SomaLogic Operating Co., Inc. as the provider of the proteomic data measured using the modified aptamer-based SomaScan® Assay. SomaScan®, SOMAmer® and SomaSignal® are trademarks of SomaLogic Operating Co., Inc.

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