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

Autor:	Ertuglu LA; Division of Nephrology, Department of Medicine (L.A.E., T.A.I.), Vanderbilt University Medical Center, Nashville, TN., Pitzer Mutchler A; Division of Clinical Pharmacology, Department of Medicine (A.P.M., S.J., C.L.L., F.E., M.S., D.J.B., D.O.K., C.L.E., B.C.K., A.K.), Vanderbilt University Medical Center, Nashville, TN., Jamison S; Division of Clinical Pharmacology, Department of Medicine (A.P.M., S.J., C.L.L., F.E., M.S., D.J.B., D.O.K., C.L.E., B.C.K., A.K.), Vanderbilt University Medical Center, Nashville, TN.; Meharry Medical College Nashville, TN (S.J.)., Laffer CL; Division of Clinical Pharmacology, Department of Medicine (A.P.M., S.J., C.L.L., F.E., M.S., D.J.B., D.O.K., C.L.E., B.C.K., A.K.), Vanderbilt University Medical Center, Nashville, TN., Elijovich F; Division of Clinical Pharmacology, Department of Medicine (A.P.M., S.J., C.L.L., F.E., M.S., D.J.B., D.O.K., C.L.E., B.C.K., A.K.), Vanderbilt University Medical Center, Nashville, TN., Saleem M; Division of Clinical Pharmacology, Department of Medicine (A.P.M., S.J., C.L.L., F.E., M.S., D.J.B., D.O.K., C.L.E., B.C.K., A.K.), Vanderbilt University Medical Center, Nashville, TN., Blackwell DJ; Division of Clinical Pharmacology, Department of Medicine (A.P.M., S.J., C.L.L., F.E., M.S., D.J.B., D.O.K., C.L.E., B.C.K., A.K.), Vanderbilt University Medical Center, Nashville, TN., Kryshtal DO; Division of Clinical Pharmacology, Department of Medicine (A.P.M., S.J., C.L.L., F.E., M.S., D.J.B., D.O.K., C.L.E., B.C.K., A.K.), Vanderbilt University Medical Center, Nashville, TN., Egly CL; Division of Clinical Pharmacology, Department of Medicine (A.P.M., S.J., C.L.L., F.E., M.S., D.J.B., D.O.K., C.L.E., B.C.K., A.K.), Vanderbilt University Medical Center, Nashville, TN., Sahinoz M; Department of Medicine (M.S.), Vanderbilt University Medical Center, Nashville, TN., Sheng Q; Department of Biostatistics (Q.S.), Vanderbilt University Medical Center, Nashville, TN., Wanjalla CN; Division of Infectious Diseases, Department of Internal Medicine (C.N.W., S.P.), Vanderbilt University Medical Center, Nashville, TN., Pakala S; Division of Infectious Diseases, Department of Internal Medicine (C.N.W., S.P.), Vanderbilt University Medical Center, Nashville, TN., Yu J; Department of Biological Sciences, Vanderbilt University, Nashville, TN (J.Y.)., Gutierrez OM; Division of Nephrology, Department of Medicine, University of Alabama at Birmingham (O.M.G.)., Kleyman TR; Vanderbilt Center for Immunobiology (VCI) (T.R.K., A.K.).; Departments of Medicine, Cell Biology, Pharmacology, and Chemical Biology, University of Pittsburgh, PA (T.R.K.)., Knollmann BC; Division of Clinical Pharmacology, Department of Medicine (A.P.M., S.J., C.L.L., F.E., M.S., D.J.B., D.O.K., C.L.E., B.C.K., A.K.), Vanderbilt University Medical Center, Nashville, TN., Ikizler TA; Division of Nephrology, Department of Medicine (L.A.E., T.A.I.), Vanderbilt University Medical Center, Nashville, TN., Kirabo A; Division of Clinical Pharmacology, Department of Medicine (A.P.M., S.J., C.L.L., F.E., M.S., D.J.B., D.O.K., C.L.E., B.C.K., A.K.), Vanderbilt University Medical Center, Nashville, TN.; Vanderbilt Center for Immunobiology (VCI) (T.R.K., A.K.).; Vanderbilt Institute for Infection, Immunology, and Inflammation (VI4) (A.K.).; Vanderbilt Institute for Global Health (VIGH) (A.K.).
Jazyk:	angličtina
Zdroj:	Hypertension (Dallas, Tex. : 1979) [Hypertension] 2024 Mar; Vol. 81 (3), pp. 516-529. Date of Electronic Publication: 2023 Sep 07.
DOI:	10.1161/HYPERTENSIONAHA.123.21285
Abstrakt:	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. Competing Interests: Disclosures None.
Databáze:	MEDLINE
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