Eicosanoid-Regulated Myeloid ENaC and Isolevuglandin Formation in Human Salt-Sensitive Hypertension.

BACKGROUND: The mechanisms by which salt increases blood pressure in people with salt sensitivity remain unclear. Our previous studies found that high sodium enters antigen-presenting cells (APCs) via the epithelial sodium channel and leads to the production of isolevuglandins and hypertension. In the current mechanistic clinical study, we hypothesized that epithelial sodium channel-dependent isolevuglandin-adduct formation in APCs is regulated by epoxyeicosatrienoic acids (EETs) and leads to salt-sensitive hypertension in humans. METHODS: Salt sensitivity was assessed in 19 hypertensive subjects using an inpatient salt loading and depletion protocol. Isolevuglandin-adduct accumulation in APCs was analyzed using flow cytometry. Gene expression in APCs was analyzed using cellular indexing of transcriptomes and epitopes by sequencing analysis of blood mononuclear cells. Plasma and urine EETs were measured using liquid chromatography-mass spectrometry. RESULTS: Baseline isolevuglandin+ APCs correlated with higher salt-sensitivity index. Isolevuglandin+ APCs significantly decreased from salt loading to depletion with an increasing salt-sensitivity index. We observed that human APCs express the epithelial sodium channel δ subunit, SGK1 (salt-sensing kinase serum/glucocorticoid kinase 1), and cytochrome P450 2S1. We found a direct correlation between baseline urinary 14,15 EET and salt-sensitivity index, whereas changes in urinary 14,15 EET negatively correlated with isolevuglandin+ monocytes from salt loading to depletion. Coincubation with 14,15 EET inhibited high-salt-induced increase in isolevuglandin+ APC. CONCLUSIONS: Isolevuglandin formation in APCs responds to acute changes in salt intake in salt-sensitive but not salt-resistant people with hypertension, and this may be regulated by renal 14,15 EET. Baseline levels of isolevuglandin+ APCs or urinary 14,15 EET may provide diagnostic tools for salt sensitivity without a protocol of salt loading.

Regulation of human salt-sensitivite hypertension by myeloid cell renin-angiotensin-aldosterone system.

Introduction: Salt sensitivity of blood pressure is a phenomenon in which blood pressure changes according to dietary sodium intake. Our previous studies found that high salt activates antigen presenting cells, resulting in the development of hypertension. The mechanisms by which salt-induced immune cell activation is regulated in salt sensitivity of blood pressure are unknown. In the current study, we investigated dietary salt-induced effects on the renin-angiotensin-aldosterone system (RAAS) gene expression in myeloid immune cells and their impact on salt sensitive hypertension in humans. Methods: We performed both bulk and single-cell sequencing analysis on immune cells with in vitro and in vivo high dietary salt treatment in humans using a rigorous salt-loading/depletion protocol to phenotype salt-sensitivity of blood pressure. We also measured plasma renin and aldosterone using radioimmunoassay. Results: We found that while in vitro high sodium exposure downregulated the expression of renin, renin binding protein and renin receptor, there were no significant changes in the genes of the renin-angiotensin system in response to dietary salt loading and depletion in vivo. Plasma renin in salt sensitive individuals tended to be lower with a blunted response to the salt loading/depletion challenge as previously reported. Discussion: These findings suggest that unlike systemic RAAS, acute changes in dietary salt intake do not regulate RAAS expression in myeloid immune cells.

The role of dietary magnesium deficiency in inflammatory hypertension.

Nearly 30% of adults consume less than the estimated average daily requirement of magnesium (Mg2+), and commonly used medications, such as diuretics, promote Mg2+ deficiency. Higher serum Mg2+ levels, increased dietary Mg2+ in-take, and Mg2+ supplementation are each associated with lower blood pressure, suggesting that Mg2+-deficiency contributes to the pathogenesis of hypertension. Antigen-presenting cells, such as monocytes and dendritic cells, are well-known to be involved in the pathogenesis of hypertension. In these cells, processes implicated as necessary for increased blood pressure include activation of the NLRP3 inflammasome, IL-1ß production, and oxidative modification of fatty acids such as arachidonic acid, forming isolevuglandins (IsoLGs). We hypothesized that increased blood pressure in response to dietary Mg2+-depletion leads to increased NLRP3, IL-1ß, and IsoLG production in antigen presenting cells. We found that a Mg2+-depleted diet (0.01% Mg2+ diet) increased blood pressure in mice compared to mice fed a 0.08% Mg2+ diet. Mg2+-depleted mice did not exhibit an increase in total body fluid, as measured by quantitative magnetic resonance. Plasma IL-1ß concentrations were increased (0.13 ± 0.02 pg/mL vs. 0.04 ± 0.02 pg/mL). Using flow cytometry, we observed increased NLRP3 and IL-1ß expression in antigen-presenting cells from spleen, kidney, and aorta. We also observed increased IsoLG production in antigen-presenting cells from these organs. Primary culture of CD11c+ dendritic cells confirmed that low extracellular Mg2+ exerts a direct effect on these cells, stimulating IL-1ß and IL-18 production. The present findings show that NLRP3 inflammasome activation and IsoLG-adduct formation are stimulated when dietary Mg2+ is depleted. Interventions and increased dietary Mg2+ consumption may prove beneficial in decreasing the prevalence of hypertension and cardiovascular disease.