Chemerin - CMKLR1 signaling contributes to immune metabolic dysfunction in salt-sensitive hypertension.

Salt-sensitivity of blood pressure (SSBP) is a significant cardiovascular risk factor, but its underlying immunometabolic mechanisms remain unclear. Chemerin, an adipose-derived inflammatory mediator linked to vascular dysfunction, was studied in 30 hypertensive adults (mean age 53.1 years; 53% female; mean BMI 32.1 kg/m2) during an inpatient salt-sensitivity protocol. Participants underwent salt-loading and salt-depletion phases over three days. Plasma and urine chemerin levels were measured, alongside immune cell phenotyping and transcriptomic profiling using CITE-seq, RNA-seq, and NanoString. Plasma chemerin increased significantly from salt-loading to salt-depletion (100.4 to 125.8 pg/mL; p = 0.008) and was higher in salt-sensitive individuals during depletion (141.2 vs. 108.6 pg/mL; p = 0.02). Plasma chemerin correlated with systolic blood pressure (SBP) during salt depletion (R2 = 0.20, p = 0.01), while urinary chemerin increased but did not correlate with SBP. In vitro, high-sodium media suppressed CMKLR1 (chemerin receptor) expression in monocytes (p < 0.01). CITE-seq revealed a 1.8-fold enrichment of CMKLR1 in classical monocytes in salt-resistant individuals compared to salt-sensitive ones, with CMKLR1 inversely correlating with ΔSBP (R2 = 0.47, p = 0.03) and ΔMAP (R2 = 0.72, p = 0.004). CMKLR1 was linked to glycolytic and oxidative phosphorylation gene upregulation, and its expression in dendritic cells correlated with urinary lactate and fumarate levels. The chemerin-CMKLR1 axis is dysregulated in SSBP, influencing monocyte and dendritic cell metabolism and blood pressure. Chemerin and CMKLR1 may serve as biomarkers and therapeutic targets for salt-sensitive hypertension.