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

Abstract

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 EET 14-15 and salt-sensitivity index, whereas changes in urinary EET 14-15 negatively correlated with isolevuglandin + monocytes from salt loading to depletion. Coincubation with EET 14-15 inhibited high-salt–induced increase in isolevuglandin + APC isolevuglandins. 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 EET 14-15. Baseline levels of isolevuglandin + APCs or urinary EET 14-15 may provide diagnostic tools for salt sensitivity without a protocol of salt loading.