Dendritic cell epithelial sodium channel induced inflammation and salt-sensitive hypertension

Demirci, Mert; Hinton, Antentor; Kirabo, Annet

doi:10.1097/mnh.0000000000000963

Cited by 5 publications

(4 citation statements)

References 72 publications

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“…At least two major conduction channels are currently known to participate in salty taste perception, namely the amiloride-sensitive and the amiloride-insensitive channels. The amiloride-sensitive channel mainly involves the epithelial sodium ion channel (ENaC), composing α-, β-, γ- and δ-subunits [ 19 , 25 ]. This class of channels exhibits high selectivity for sodium ions.…”

Section: Salty Taste Perception Mechanism and Sodium Salt Reduction S...mentioning

confidence: 99%

Progress in Multisensory Synergistic Salt Reduction

Liu,

Gu,

Zheng

et al. 2024

Foods

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Excessive salt intake, primarily from sodium chloride prevalent in modern food processing, poses a significant public health risk associated with hypertension, cardiovascular diseases and stroke. Researchers worldwide are exploring approaches to reduce salt consumption without compromising food flavor. One promising method is to enhance salty taste perception using multisensory synergies, leveraging gustatory, olfactory, auditory, visual, tactile and trigeminal senses to decrease salt intake while preserving food taste. This review provides a comprehensive overview of salt usage in foods, mechanisms of salty taste perception and evaluation methods for saltiness. Various strategies for reducing salt consumption while maintaining food flavor are examined, with existing salt reduction methods’ advantages and limitations being critically analyzed. A particular emphasis is placed on exploring the mechanisms and potential of multisensory synergy in salt reduction. Taste interactions, olfactory cues, auditory stimulation, visual appearance and tactile sensations in enhancing saltiness perception are discussed, offering insights into developing nutritious, appealing low-sodium foods. Furthermore, challenges in current research are highlighted, and future directions for effective salt reduction strategies to promote public health are proposed. This review aims to establish a scientific foundation for creating healthier, flavorful low-sodium food options that meet consumer preferences and wellness needs.

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Section: Salty Taste Perception Mechanism and Sodium Salt Reduction S...mentioning

confidence: 99%

Progress in Multisensory Synergistic Salt Reduction

Liu,

Gu,

Zheng

et al. 2024

Foods

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“…The mutations in the SCNN1A gene are extremely rare and occur in its extracellular domain, triggering its activation . The SCNN1D gene is minimally expressed in the kidney and may cause hypertension via inflammation in the kidney [ 29 , 30 ].…”

Section: Introductionmentioning

confidence: 99%

Update in genetic and epigenetic causes of hypertension

Mani

2024

Cell. Mol. Life Sci.

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Hypertension is a heritable disease that affects one-fourth of the population and accounts for about 50% of cardiovascular deaths. The genetic basis of hypertension is multifaceted, involving both monogenic and most commonly complex polygenic forms. With the advent of the human genome project, genome-wide association studies (GWAS) have identified a plethora of loci linked to hypertension by examining common genetic variations. It's notable, however, that the majority of these genetic variants do not affect the protein-coding sequences, posing a considerable obstacle in pinpointing the actual genes responsible for hypertension. Despite these challenges, precise mapping of GWAS-identified loci is emerging as a promising strategy to reveal novel genes and potential targets for the pharmacological management of blood pressure. This review provides insight into the monogenic and polygenic causes of hypertension. Special attention is given to PRDM6, among the earliest functionally characterized GWAS-identified genes. Moreover, this review delves into the roles of genes contributing to renal and vascular forms of hypertension, offering insights into their genetic and epigenetic mechanisms of action.

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“…6,9 Thus, therapeutic strategies to reduce Na + intake or signaling may reduce inflammation and hypertension. 10 The epithelial sodium channel (ENaC), which is implicated in the pathogenesis of SSBP [11][12][13] , has been studied extensively in the kidney, where it regulates electrolyte and volume balance. Our studies indicate that dendritic cell (DC) entry of extracellular Na + requires ENaC, which is then exchanged for Ca 2+ via the Na + /Ca 2+ exchanger with the resultant activation of protein kinase C (PKC).…”

Section: Introductionmentioning

confidence: 99%

“…6,9 Thus, therapeutic strategies to reduce Na + intake or signaling may reduce inflammation and hypertension. 10…”

Section: Introductionmentioning

confidence: 99%

Myeloid Cell Glucocorticoid, Not Mineralocorticoid Receptor Signaling, Contributes to Salt-Sensitive Hypertension in Humans via Cortisol

Albritton,

Demirci,

Neikirk

et al. 2024

Preprint

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BACKGROUNDSalt sensitivity of blood pressure (SSBP) is an independent risk factor for cardiovascular morbidity and mortality, yet the etiology is poorly understood. We previously found that serum/glucocorticoid-regulated kinase 1 (SGK1) and epoxyeicosatrienoic acids (EETs) regulate epithelial sodium channel (ENaC)-dependent sodium entry into monocyte-derived antigen-presenting cells (APCs) and activation of NADPH oxidase, leading to the formation of isolevuglandins (IsoLGs) in SSBP. Whereas aldosterone via the mineralocorticoid receptor (MR) activates SGK1 leading to hypertension, our past findings indicate that levels of plasma aldosterone do not correlate with SSBP, and there is little to no MR expression in APCs. Thus, we hypothesized that cortisol acting via the glucocorticoid receptor (GR), not the MR in APCs mediates SGK1 actions to induce SSBP.METHODSWe performed cellular indexing of transcriptomes and epitopes by sequencing (CITE-Seq) analysis on peripheral blood mononuclear cells of humans rigorously phenotyped for SSBP using an inpatient salt loading/depletion protocol to determine expression of MR, GR, and SGK1 in immune cells. In additional experiments, we performed bulk transcriptomic analysis on isolated human monocytes followingin vitrotreatment with high salt from a separate cohort. We then measured urine and plasma cortisol, cortisone, renin, and aldosterone. Subsequently, we measured the association of these hormones with changes in systolic, diastolic, mean arterial pressure and pulse pressure as well as immune cell activation via IsoLG formation.RESULTSWe found that myeloid APCs predominantly express the GR and SGK1 with no expression of the MR. Expression of the GR in APCs increased after salt loading and decreased with salt depletion in salt-sensitive but not salt-resistant people and was associated with increased expression ofSGK1. Moreover, we found that plasma and urine cortisol/cortisone but not aldosterone/renin correlated with SSBP and APCs activation via IsoLGs. We also found that cortisol negatively correlates with EETs.CONCLUSIONOur findings suggest that renal cortisol signaling via the GR but not the MR in APCs contributes to SSBP via cortisol. Urine and plasma cortisol may provide an important currently unavailable feasible diagnostic tool for SSBP. Moreover, cortisol-GR-SGK1-ENaC signaling pathway may provide treatment options for SSBP.Novelty and RelevanceWhat Is New?Although salt sensitivity is a major risk factor for cardiovascular morbidity and mortality, the mechanisms underlying the salt sensitivity of blood pressure (SSBP) are poorly understood.High salt modifies glucocorticoid-receptor expression in antigen-presenting cells (APCs), suggesting a critical role of glucocorticoids in SSBP.Elevated glucocorticoid receptor (GR) expression compared to mineralocorticoid receptor (MR) expression in APCs provides evidence for a GR-dependent pathway to SSBP. Isolevuglandins (IsoLGs) increased in APCsin vitroafter hydrocortisone treatment compared to aldosterone treatment, indicating that cortisol was the predominant driver of IsoLG production in these cells.Our studies suggest a mechanism forSGK1expression through GR activation by cortisol that differs from the currently accepted mechanism for SSBP pathogenesis.What Is Relevant?Although aldosterone has been used to study SSBP, there has been no consideration of cortisol as a major driver of the condition.Understanding alternative inflammatory pathways that affect SSBP may provide insights into the mechanism of SSBP and suggest a range of therapeutic targets.Our studies may provide a practical approach to understanding and treating salt-sensitive hypertension.Clinical/Pathophysiological Implications?Our findings firmly support a GR-dependent signaling pathway for activating SSBP viaSGK1expression. A cortisol-driven mechanism could provide a practical approach for targeted treatments for salt-sensitive hypertension. Moreover, it could pave the way for a diagnostic approach.

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Dendritic cell epithelial sodium channel induced inflammation and salt-sensitive hypertension

Cited by 5 publications

References 72 publications

Progress in Multisensory Synergistic Salt Reduction

Progress in Multisensory Synergistic Salt Reduction

Update in genetic and epigenetic causes of hypertension

Myeloid Cell Glucocorticoid, Not Mineralocorticoid Receptor Signaling, Contributes to Salt-Sensitive Hypertension in Humans via Cortisol

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