Abstract 4143897: Monocyte regulation of magnesium during salt sensitivity of blood pressure

Background: Dietary magnesium (Mg +2 ) deficiency has been linked to hypertension, chronic kidney disease, and cardiovascular disease. High sodium intake and reduced dietary Mg +2 consumption are associated with elevated blood pressure. We have previously shown a role for monocyte-producing isolevuglandins (IsoLGs) in the pathogenesis of salt-sensitivity of blood pressure (SSBP) and, in a separate study, dietary Mg +2 deficiency. However, it is unknown whether decreased Mg +2 contributes to IsoLG-adduct formation in SSBP[DM1] [PA2] . We hypothesized that decreased Mg +2 transport into monocytes leads to IsoLG-adduct formation during SSBP. Methods: In vitro studies were performed on isolated monocytes from 11 healthy patients treated with normal salt (150mM) and high salt (190mM) and submitted for RNAseq. In vivo studies were performed on 9 hypertensive subjects enrolled in an acute inpatient protocol of salt loading (SL) (460mmoL/24 hrs) and salt depletion (SD) (10mmoL/24 hrs, and furosemide 40mg x 3). Isolated PBMCs were analyzed using CITE-seq (cellular indexing of transcriptomes and epitopes). IsoLG-containing classical monocytes were identified using flow cytometry. Pearson correlation was used to analyze the associations. Salt sensitivity index (SSI) is the difference in SL versus SD systolic blood pressure. Results: Using an unbiased approach, I utilized the Harmonizome 3.0 database to identify genes involved in Mg +2 homeostasis. I identified 75 genes and cross-referenced them with our bulk RNAseq data. Analysis of differentially expressed genes demonstrated a downregulation in Mg +2 transporter 1 (log2FC=-0.44, p-adj=0.01) and cyclin M2 ( CNNM2 ) (log2FC=-0.34, p-adj=0.006) with an upregulation of solute carrier family 41 member 1 (log2FC=0.39, p-adj=0.006) in response to high salt media. In our inpatient cohort, baseline monocyte expression of CNNM2 negatively correlated with SSI (r=-0.72; p=0.045). There was a positive correlation between baseline CNNM2 with baseline %IsoLG+ classical monocytes, although not statistically significant (r= 0.69; p=0.06). Similarly, there was a trend of negative correlation of baseline %IsoLG+ classical monocytes with increasing SSI, though not significant (r=-0.68; p=0.06). Conclusions: Our preliminary findings suggest high salt downregulates Mg +2 transporters and decreased Mg +2 transport are potentially associated with monocyte-derived IsoLG-adduct formation, thus exacerbating the inflammatory response in SSBP.