SVEP1 Upregulation Is a Prominent Molecular Response to Dietary Sodium Loading and Correlates with Inverse Salt Sensitivity.

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), 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) and 8th (p=2.19×10) 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.