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Cell Rep. 2017 Oct 24;21(4):1009-1020. doi: 10.1016/j.celrep.2017.10.002.

Dendritic Cell Amiloride-Sensitive Channels Mediate Sodium-Induced Inflammation and Hypertension.

Author information

1
Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
2
Department of Biochemistry, Vanderbilt University, Nashville, TN, USA.
3
Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA.
4
Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA.
5
Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA. Electronic address: annet.kirabo@vanderbilt.edu.

Abstract

Sodium accumulates in the interstitium and promotes inflammation through poorly defined mechanisms. We describe a pathway by which sodium enters dendritic cells (DCs) through amiloride-sensitive channels including the alpha and gamma subunits of the epithelial sodium channel and the sodium hydrogen exchanger 1. This leads to calcium influx via the sodium calcium exchanger, activation of protein kinase C (PKC), phosphorylation of p47phox, and association of p47phox with gp91phox. The assembled NADPH oxidase produces superoxide with subsequent formation of immunogenic isolevuglandin (IsoLG)-protein adducts. DCs activated by excess sodium produce increased interleukin-1β (IL-1β) and promote T cell production of cytokines IL-17A and interferon gamma (IFN-γ). When adoptively transferred into naive mice, these DCs prime hypertension in response to a sub-pressor dose of angiotensin II. These findings provide a mechanistic link between salt, inflammation, and hypertension involving increased oxidative stress and IsoLG production in DCs.

KEYWORDS:

ENaC; NADPH oxidase; amiloride; calcium; dendritic cells; hypertension; isolevuglandins; oxidative stress; sodium chloride

PMID:
29069584
PMCID:
PMC5674815
DOI:
10.1016/j.celrep.2017.10.002
[Indexed for MEDLINE]
Free PMC Article

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