Inverse Salt Sensitivity of Blood Pressure: Mechanisms and Potential Relevance for Prevention of Cardiovascular Disease

Felder, Robin A.; Gildea, John J; Xu, Peng; Yue, Wei; Armando, Inés; Carey, Robert M.; José, Pedro A.

doi:10.1007/s11906-022-01201-9

Cited by 11 publications

(19 citation statements)

References 138 publications

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“…Hypertension can be caused or exacerbated by an increase in the intake of salt, in individuals with SS [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 17 , 18 , 19 , 29 , 36 , 37 , 38 , 39 , 40 ]. However, about 11% of individuals have increased BP when the intake of salt is very low (<1.2–3 g/day) [ 23 , 24 , 25 , 47 , 84 , 85 ]. In one recent long-term study (median 16 years, IQR 12–17 years [ 26 ]) individuals with ISS had a 15-fold increase of end-organ damage and mortality compared with individuals with SR.…”

Section: Discussionmentioning

confidence: 99%

“…We recently showed that one subunit of the Na + channel (alpha ENaC) is involved in the etiology of ISS [ 117 ]. Here, we find that the RPT apical Na + /myoinositol cotransporter 2 (aka SMIT2, SLC5A11 , and SGLT6 ) containing homozygous SNP at rs11074656 is decreased in individuals with ISS [ 47 ]. In addition to the SNP-dependent decrease in expression of SLC5A11, the reduced expression of SLC5A11 in low salt conditions in ISS may be due to SLC5A11 being a known positively regulated specific target of the transcription factor, NRF2 [ 118 ].…”

Section: Discussionmentioning

confidence: 99%

“…Briefly, we used the statistical tests to classify participants who successfully completed our salt diets (based on 24-h urine salt balance evaluation) into ISS, SR, and SS. Statistical justification for the cutoff points between the ISS, SR, and SS groups was performed, as previously published [ 47 ].…”

Section: Methodsmentioning

confidence: 99%

“…Angiotensin (Ang) type 1 receptor (AT 1 R) is an antinatriuretic G protein-coupled receptor previously shown to increase calcium signaling via Ang II in ISS [ 20 ]. Other components of the renin-angiotensin system (RAS) may also play a role in the pathogenesis of ISS, such as aminopeptidase N (APN) which converts Ang III into angiotensin IV (Ang IV), reducing the levels of Ang III, the preferred endogenous agonist for the natriuretic Ang II type 2 receptor (AT 2 R), resulting in sodium retention and elevated BP [ 46 , 47 ]. APN has variable effects on BP [ 48 , 49 , 50 ].…”

Section: Introductionmentioning

confidence: 99%

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Inverse Salt Sensitivity of Blood Pressure Is Associated with an Increased Renin-Angiotensin System Activity

Gildea

Schiermeyer

et al. 2022

Biomedicines

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High and low sodium diets are associated with increased blood pressure and cardiovascular morbidity and mortality. The paradoxical response of elevated BP in low salt diets, aka inverse salt sensitivity (ISS), is an understudied vulnerable 11% of the adult population with yet undiscovered etiology. A linear relationship between the number of single nucleotide polymorphisms (SNPs) in the dopamine D2 receptor (DRD2, rs6276 and 6277), and the sodium myo-inositol cotransporter 2 (SLC5A11, rs11074656), as well as decreased expression of these two genes in urine-derived renal proximal tubule cells (uRPTCs) isolated from clinical study participants suggest involvement of these cells in ISS. Insight into this newly discovered paradoxical response to sodium is found by incubating cells in low sodium (LS) conditions that unveil cell physiologic differences that are then reversed by mir-485-5p miRNA blocker transfection and bypassing the genetic defect by DRD2 re-expression. The renin-angiotensin system (RAS) is an important counter-regulatory mechanism to prevent hyponatremia under LS conditions. Oversensitive RAS under LS conditions could partially explain the increased mortality in ISS. Angiotensin-II (AngII, 10 nmol/L) increased sodium transport in uRPTCs to a greater extent in individuals with ISS than SR. Downstream signaling of AngII is verified by identifying lowered expression of nuclear factor erythroid 2-related factor 2 (NRF2), CCCTC-binding factor (CTCF), and manganese-dependent mitochondrial superoxide dismutase (SOD2) only in ISS-derived uRPTCs and not SR-derived uRPTCs when incubated in LS conditions. We conclude that DRD2 and SLC5A11 variants in ISS may cause an increased low sodium sensitivity to AngII and renal sodium reabsorption which can contribute to inverse salt-sensitive hypertension.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Inverse Salt Sensitivity of Blood Pressure Is Associated with an Increased Renin-Angiotensin System Activity

Gildea

Schiermeyer

et al. 2022

Biomedicines

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“…Nevertheless, in the above studies, vascular reactivity to acetylcholine and nitroprusside are not impaired, indicating a normal nitric oxide system. Therefore, aberrations in other counter-regulatory pathways, (eg, dopaminergic pathway, eicosanoids), participate in the pathogenesis of essential hypertension [25,26,[35][36][37][38][39][40][41][42][43].…”

Section: Role Of the Renal Dopaminergic System In Essential Hypertensionmentioning

confidence: 99%

Dopamine Receptor D1R and D3R and GRK4 Interaction in Hypertension

et al. 2023

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Essential hypertension is caused by the interaction of genetic, behavioral, and environmental factors. Abnormalities in the regulation of renal ion transport cause essential hypertension. The renal dopaminergic system, which inhibits sodium transport in all the nephron segments, is responsible for at least 50% of renal sodium excretion under conditions of moderate sodium excess. Dopaminergic signals are transduced by two families of receptors that belong to the G protein-coupled receptor (GPCR) superfamily. D 1 -like receptors (D 1 R and D 5 R) stimulate, while D2-like receptors (D 2 R, D 3 R, and D 4 R) inhibit adenylyl cyclases. The dopamine receptor subtypes, themselves, or by their interactions, regulate renal sodium transport and blood pressure. We review the role of the D 1 R and D 3 R and their interaction in the natriuresis associated with volume expansion. The D 1 R-and D 3 R-mediated inhibition of renal sodium transport involves PKA and PKC-dependent and -independent mechanisms. The D 3 R also increases the degradation of NHE3 via USP-mediated ubiquitinylation. Although deletion of Drd1 and Drd3 in mice causes hypertension, DRD1 polymorphisms are not always associated with human essential hypertension and polymorphisms in DRD3 are not associated with human essential hypertension. The impaired D 1 R and D 3 R function in hypertension is related to their hyper-phosphorylation; GRK4γ isoforms, R65L, A142V, and A486V, hyper-phosphorylate and desensitize D 1 R and D 3 R. The GRK4 locus is linked to and GRK4 variants are associated with high blood pressure in humans. Thus, GRK4, by itself, and by regulating genes related to the control of blood pressure may explain the "apparent" polygenic nature of essential hypertension.

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Effect of Dietary Sodium on Blood Pressure

Gupta,

Lewis,

Varady

et al. 2023

JAMA

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ImportanceDietary sodium recommendations are debated partly due to variable blood pressure (BP) response to sodium intake. Furthermore, the BP effect of dietary sodium among individuals taking antihypertensive medications is understudied.ObjectivesTo examine the distribution of within-individual BP response to dietary sodium, the difference in BP between individuals allocated to consume a high- or low-sodium diet first, and whether these varied according to baseline BP and antihypertensive medication use.Design, Setting, and ParticipantsProspectively allocated diet order with crossover in community-based participants enrolled between April 2021 and February 2023 in 2 US cities. A total of 213 individuals aged 50 to 75 years, including those with normotension (25%), controlled hypertension (20%), uncontrolled hypertension (31%), and untreated hypertension (25%), attended a baseline visit while consuming their usual diet, then completed 1-week high- and low-sodium diets.InterventionHigh-sodium (approximately 2200 mg sodium added daily to usual diet) and low-sodium (approximately 500 mg daily total) diets.Main Outcomes and MeasuresAverage 24-hour ambulatory systolic and diastolic BP, mean arterial pressure, and pulse pressure.ResultsAmong the 213 participants who completed both high- and low-sodium diet visits, the median age was 61 years, 65% were female and 64% were Black. While consuming usual, high-sodium, and low-sodium diets, participants’ median systolic BP measures were 125, 126, and 119 mm Hg, respectively. The median within-individual change in mean arterial pressure between high- and low-sodium diets was 4 mm Hg (IQR, 0-8 mm Hg; P &lt; .001), which did not significantly differ by hypertension status. Compared with the high-sodium diet, the low-sodium diet induced a decline in mean arterial pressure in 73.4% of individuals. The commonly used threshold of a 5 mm Hg or greater decline in mean arterial pressure between a high-sodium and a low-sodium diet classified 46% of individuals as “salt sensitive.” At the end of the first dietary intervention week, the mean systolic BP difference between individuals allocated to a high-sodium vs a low-sodium diet was 8 mm Hg (95% CI, 4-11 mm Hg; P &lt; .001), which was mostly similar across subgroups of age, sex, race, hypertension, baseline BP, diabetes, and body mass index. Adverse events were mild, reported by 9.9% and 8.0% of individuals while consuming the high- and low-sodium diets, respectively.Conclusions and RelevanceDietary sodium reduction significantly lowered BP in the majority of middle-aged to elderly adults. The decline in BP from a high- to low-sodium diet was independent of hypertension status and antihypertensive medication use, was generally consistent across subgroups, and did not result in excess adverse events.Trial RegistrationClinicalTrials.gov Identifier: NCT04258332

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Inverse Salt Sensitivity of Blood Pressure: Mechanisms and Potential Relevance for Prevention of Cardiovascular Disease

Cited by 11 publications

References 138 publications

Inverse Salt Sensitivity of Blood Pressure Is Associated with an Increased Renin-Angiotensin System Activity

Inverse Salt Sensitivity of Blood Pressure Is Associated with an Increased Renin-Angiotensin System Activity

Dopamine Receptor D1R and D3R and GRK4 Interaction in Hypertension

Effect of Dietary Sodium on Blood Pressure

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