Effects Of Dietary Salt Intake Research Articles

Causal relationship between dietary salt intake and dementia risk: Mendelian randomization study.

Observational research has indicated a potential link between dietary salt intake and susceptibility to dementia. However, it is important to note that these types of studies are prone to the issues of reverse causation and residual confounding. Therefore, we conducted a two-sample Mendelian randomization (MR) study to explore the causality. To explore the causal relationship between them, this Mendelian randomization (MR) study incorporated summary statistics of dietary salt intake and dementia. We estimated the causality between salt intake and the risk of overall dementia andvarious subtypes of dementia, including Alzheimer's disease (AD), Vascular dementia (VaD), and Lewy body dementia (LBD). The inverse variance-weighted (IVW) method was the major MR analysis. To conduct sensitivity analyses, we employed various MR methods, the pleiotropy residual sum and outlier (MR-PRESSO) method, and the leave-one-out approach. The MR-Egger intercept and Cochran's Q test were conducted to test pleiotropy and heterogeneityrespectively. A suggestive association was observed for genetically predicted higher dietary salt intake and increased risk of overalldementia in the European ancestry [odds ratio (OR): 1.542; 95% confidence interval (95% CI): 1.095-2.169; P = 0.013]. The causal relationship between dietary salt intake and overalldementia is robust with respect to the choice of statistical methods and is validated through extensive sensitivity analyses that guard against various model assumption violations. Meanwhile, no clear heterogeneity or pleiotropy was identified. However, we failed to detect a causal effect of dietary salt intake on the risk of various dementia subtypes. The results of this research present strong evidence that established a significant association between dietary salt intake and the likelihood of developing dementia. These findings reinforce the notion that the amount of dietary salt intake plays a crucial role in determining the risk of acquiring this cognitive condition. By establishing a definitive correlation, this study highlights the importance of reducing salt consumption as a preventive measure against dementia.

Measured sodium excretion is associated with cardiovascular outcomes in non-dialysis CKD patients: results from the KNOW-CKD study.

There are insufficient studies on the effect of dietary salt intake on cardiovascular (CV) outcomes in chronic kidney disease (CKD) patients, and there is no consensus on the sodium (Na) intake level that increases the risk of CV disease in CKD patients. Therefore, we investigated the association between dietary salt intake and CV outcomes in CKD patients. In the Korean cohort study for Outcome in patients with CKD (KNOW-CKD), 1,937 patients were eligible for the study, and their dietary Na intake was estimated using measured 24h urinary Na excretion. The primary outcome was a composite of CV events and/or all-cause death. The secondary outcome was a major adverse cardiac event (MACE). Among 1,937 subjects, there were 205 (10.5%) events for the composite outcome and 110 (5.6%) events for MACE. Compared to the reference group (urinary Na excretion< 2.0g/day), the group with the highest measured 24h urinary Na excretion (urinary Na excretion ≥ 8.0g/day) was associated with increased risk of both the composite outcome (hazard ratio 3.29 [95% confidence interval 1.00-10.81]; P = 0.049) and MACE (hazard ratio 6.28 [95% confidence interval 1.45-27.20]; P = 0.013) in a cause-specific hazard model. Subgroup analysis also showed a pronounced association between dietary salt intake and the composite outcome in subgroups of patients with abdominal obesity, female, lower estimated glomerular filtration rate (< 60 ml/min per 1.73m2), no overt proteinuria, or a lower urinary potassium-to-creatinine ratio (< 46 mmol/g). A high-salt diet is associated with CV outcomes in non-dialysis CKD patients.

Excessive salt intake reduces bone density in the general female population.

Osteoporosis is a multifactorial disorder in which nutrition is associated with its onset and progression. Excessive salt intake is closely associated with the onset and progression of various diseases, such as osteoporosis and hypertension. We investigated the effects of dietary salt intake on bone density in the general female population. In 884 female participants (60.1 ± 10.1 years old) who visited our hospital for an annual physical checkup, salt intake (g/day) was assessed using a spot urine sample, and bone density was evaluated as a speed of sound (m/s) of ultrasonic pulses in a calcaneus by quantitative ultrasound. We investigated the relationship between bone density and salt intake and the differences in bone density or salt intake between the presence and absence of lifestyle-related diseases such as hypertension, diabetes mellitus and dyslipidaemia. The average bone density and salt intake were 1497 ± 26 m/s and 8.5 ± 1.8 g/day, respectively. Univariate and multivariate regression analyses revealed that bone density was significantly negatively associated with salt intake. Bone density was lower, and salt intake was higher in participants with hypertension, diabetes mellitus and dyslipidaemia than in those without. After adjusting for age, hypertension, diabetes mellitus and dyslipidaemia, bone density was negatively correlated with salt intake. We confirmed that excessive salt intake reduces bone density independently of age and lifestyle-related diseases in the general female population. Since dietary salt intake is a modifiable factor, osteoporosis can be prevented by dietary intervention, including salt reduction.

Effect of Dietary Salt Intake on Risk of Gastric Cancer: A Systematic Review and Meta-Analysis of Case-Control Studies.

Aim: The effect of dietary salt intake on the risk of gastric cancer is not clear. A meta-analysis was performed to estimate the association between dietary salt intake and the risk of gastric cancer. Methods: Three major databases were searched to retrieve case-control studies published in English before 1 July 2022. Random effects model analysis was used to obtain the pooled odds ratios (ORs) and 95% confidence intervals (CIs) of the association between dietary salt intake and risk of gastric cancer. Subgroup analyses were used to identify possible sources of heterogeneity. Results: Thirty-eight case-control studies were included in this meta-analysis (total population: n = 37,225). The pooled ORs showed a significantly positive association between high salt intake and gastric cancer compared with low salt intake (OR = 1.55, 95% CI (1.45, 1.64); p < 0.001). In subgroup meta-analysis for geographic region, estimation method for dietary salt intake and the source of controls, this association was not changed. Conclusion: Higher dietary salt intake increased the risk of gastric cancer. This study has implications for the prevention of gastric cancer.

Measured sodium excretion is associated with CKD progression: results from the KNOW-CKD study.

Diet is a modifiable factor of chronic kidney disease (CKD) progression. However, the effect of dietary salt intake on CKD progression remains unclear. Therefore, we analyzed the effect of dietary salt intake on renal outcome in Korean patients with CKD. We measured 24-h urinary sodium (Na) excretion as a marker of dietary salt intake in the prospective, multi-center, longitudinal KoreaN cohort study for Outcome in patients With CKD (KNOW-CKD). Data were analyzed from CKD patients at Stages G3a to G5 (n = 1254). We investigated the association between dietary salt intake and CKD progression. Patients were divided into four quartiles of dietary salt intake, which was assessed using measured 24-h urinary Na excretion. The study endpoint was composite renal outcome, which was defined as either halving the estimated glomerular filtration rate or developing end-stage renal disease. During a median (interquartile range) follow-up of 4.3 (2.8-5.8) years, 480 (38.7%) patients developed the composite renal event. Compared with the reference group (Q2, urinary Na excretion: 104.2 ≤ Na excretion < 145.1 mEq/day), the highest quartile of measured 24-h urinary Na excretion was associated with risk of composite renal outcome [Q4, urinary Na excretion ≥192.9 mEq/day, hazard ratio 1.8 (95% confidence interval 1.12-2.88); P = 0.015] in a multivariable hazards model. Subgroup analyses showed that high-salt intake was particularly associated with a higher risk of composite renal outcome in women, in patients <60 years of age, in those with uncontrolled hypertension and in those with obesity. High salt intake was associated with increased risk of progression in CKD.

Effect of dietary salt intake on epithelial Na+ channels (ENaCs) in the hypothalamus of Dahl salt-sensitive rats.

All three epithelial Na+ channel (ENaC) subunits (α, β, and γ) and the mineralocorticoid receptor (MR), a known regulator of ENaC, are located in vasopressin (VP) synthesizing magnocellular neurons in the hypothalamic supraoptic (SON) and paraventricular (PVN) nuclei. Our previous study showed that ENaC mediates a Na+ leak current that affects the steady‐state membrane potential of VP neurons. This study was conducted in Dahl salt‐sensitive (Dahl‐SS) rats to determine if any abnormal responses in the expression of ENaC subunits and MR occur in the hypothalamus and kidney in response to a high dietary salt intake. After 21 days of high salt consumption, Dahl‐SS rat resulted in a significant increase in γ ENaC expression and exhibited proteolytic cleavage of this subunit compared to Sprague–Dawley (SD) rats. Additionally, Dahl‐SS rats had dense somato‐dendritic γ ENaC immunoreactivity in VP neurons, which was absent in SD rats. In contrast, SD rats fed a high salt diet had significantly decreased α ENaC subunit expression in the kidney and MR expression in the hypothalamus. Plasma osmolality measured daily for 22 days demonstrated that Dahl‐SS rats fed a high salt diet had a steady increase in plasma osmolality, whereas SD rats had an initial increase that decreased to baseline levels. Findings from this study demonstrate that Dahl‐SS rats lack a compensatory mechanism to down regulate ENaC during high dietary salt consumption, which may contribute to the development of hypertension.

Dietary sodium induces a redistribution of the tubular metabolic workload.

Key points Body Na+ content is tightly controlled by regulated urinary Na+ excretion.The intrarenal mechanisms mediating adaptation to variations in dietary Na+ intake are incompletely characterized.We confirmed and expanded observations in mice that variations in dietary Na+ intake do not alter the glomerular filtration rate but alter the total and cell‐surface expression of major Na+ transporters all along the kidney tubule.Low dietary Na+ intake increased Na+ reabsorption in the proximal tubule and decreased it in more distal kidney tubule segments.High dietary Na+ intake decreased Na+ reabsorption in the proximal tubule and increased it in distal segments with lower energetic efficiency.The abundance of apical transporters and Na+ delivery are the main determinants of Na+ reabsorption along the kidney tubule.Tubular O2 consumption and the efficiency of sodium reabsorption are dependent on sodium diet. Na+ excretion by the kidney varies according to dietary Na+ intake. We undertook a systematic study of the effects of dietary salt intake on glomerular filtration rate (GFR) and tubular Na+ reabsorption. We examined the renal adaptive response in mice subjected to 7 days of a low sodium diet (LSD) containing 0.01% Na+, a normal sodium diet (NSD) containing 0.18% Na+ and a moderately high sodium diet (HSD) containing 1.25% Na+. As expected, LSD did not alter measured GFR and increased the abundance of total and cell‐surface NHE3, NKCC2, NCC, α‐ENaC and cleaved γ‐ENaC compared to NSD. Mathematical modelling predicted that tubular Na+ reabsorption increased in the proximal tubule but decreased in the distal nephron because of diminished Na+ delivery. This prediction was confirmed by the natriuretic response to diuretics targeting the thick ascending limb, the distal convoluted tubule or the collecting system. On the other hand, HSD did not alter measured GFR but decreased the abundance of the aforementioned transporters compared to NSD. Mathematical modelling predicted that tubular Na+ reabsorption decreased in the proximal tubule but increased in distal segments with lower transport efficiency with respect to O2 consumption. This prediction was confirmed by the natriuretic response to diuretics. The activity of the metabolic sensor adenosine monophosphate‐activated protein kinase (AMPK) was related to the changes in tubular Na+ reabsorption. Our data show that fractional Na+ reabsorption is distributed differently according to dietary Na+ intake and induces changes in tubular O2 consumption and sodium transport efficiency.

Effect of dietary salt intake on epithelial Na+ channels (ENaC) in vasopressin magnocellular neurosecretory neurons in the rat supraoptic nucleus.

Key points A growing body of evidence suggests that epithelial Na+ channels (ENaCs) in the brain play a significant role in the regulation of blood pressure; however, the brain structures that mediate the effect are not well understood.Because vasopressin (VP) neurons play a pivotal role in coordinating neuroendocrine and autonomic responses to maintain cardiovascular homeostasis, a basic understanding of the regulation and activity of ENaC in VP neurons is of great interest.We show that high dietary salt intake caused an increase in the expression and activity of ENaC which resulted in the steady state depolarization of VP neurons.The results help us understand one of the mechanisms underlying how dietary salt intake affects the activity of VP neurons via ENaC activity. All three epithelial Na+ channel (ENaC) subunits (α, β and γ) are located in vasopressin (VP) magnocellular neurons in the hypothalamic supraoptic (SON) and paraventricular nuclei. Our previous study demonstrated that ENaC mediates a Na+ leak current that affects the steady state membrane potential in VP neurons. In the present study, we evaluated the effect of dietary salt intake on ENaC regulation and activity in VP neurons. High dietary salt intake for 7 days caused an increase in expression of β‐ and γENaC subunits in the SON and the translocation of αENaC immunoreactivity towards the plasma membrane. Patch clamp experiments on hypothalamic slices showed that the mean amplitude of the putative ENaC currents was significantly greater in VP neurons from animals that were fed a high salt diet compared with controls. The enhanced ENaC current contributed to the more depolarized basal membrane potential observed in VP neurons in the high salt diet group. These findings indicate that high dietary NaCl intake enhances the expression and activity of ENaCs, which augments synaptic drive by depolarizing the basal membrane potential close to the action potential threshold during hormonal demand. However, ENaCs appear to have only a minor role in the regulation of the firing activity of VP neurons in the absence of synaptic inputs as neither the mean intraburst frequency, burst duration, nor interspike interval variability of phasic bursting activity was affected. Moreover, ENaC activity did not affect the initiation, sustention, or termination of the phasic bursting generated in an intrinsic manner without synaptic inputs.

The relationship between dietary salt intake and ambulatory blood pressure variability in non-diabetic hypertensive patients

High dietary salt intake was reported to increase blood pressure by numerous studies, but no study has investigated the effect of dietary salt intake on blood pressure variability (BPV). This study aimed to determine if daily salt intake is related to ambulatory BPV. The study included 136 primary hypertensive patients (92 male, 44 female) with a mean age of 50.7±11.1 years. All the patients underwent 24-h ambulatory blood pressure monitoring to determine both the 24-h systolic and 24-h diastolic BPV. 24-h urine sodium was measured. The correlation between BPV and 24-h urinary sodium was investigated. Logarithmic transformation of 24-h urinary sodium [log(24-h urinary sodium)] was positively correlated with the mean 24-h systolic ARV, and nighttime systolic ARV (r=0.371 and p=0.001, r=0.329 and p=0.028, respectively). Similarly, log(24-h urinary sodium) was positively correlated with mean 24-h diastolic ARV and nighttime diastolic ARV (r=0.381 and p=0.001, r=0.320 and p=0.020 respectively). Log(24-h urinary sodium) was an independent predictor of BPV based on multivariate regression analysis. Dietary salt intake might play a role in the pathogenesis of ambulatory BPV.

The relationship between dietary salt intake and ambulatory blood pressure variability in non-diabetic hypertensive patients

High dietary salt intake was reported to increase blood pressure by numerous studies, but no study has investigated the effect of dietary salt intake on blood pressure variability (BPV). This study aimed to determine if daily salt intake is related to ambulatory BPV. The study included 136 primary hypertensive patients (92 male, 44 female) with a mean age of 50.7±11.1 years. All the patients underwent 24-h ambulatory blood pressure monitoring to determine both the 24-h systolic and 24-h diastolic BPV. 24-h urine sodium was measured. The correlation between BPV and 24-h urinary sodium was investigated. Logarithmic transformation of 24-h urinary sodium [log(24-h urinary sodium)] was positively correlated with the mean 24-h systolic ARV, and nighttime systolic ARV (r=0.371 and p=0.001, r=0.329 and p=0.028, respectively). Similarly, log(24-h urinary sodium) was positively correlated with mean 24-h diastolic ARV and nighttime diastolic ARV (r=0.381 and p=0.001, r=0.320 and p=0.020 respectively). Log(24-h urinary sodium) was an independent predictor of BPV based on multivariate regression analysis. Dietary salt intake might play a role in the pathogenesis of ambulatory BPV.

Reported Amount of Salt Added to Food Is Associated with Increased All-Cause and Cancer-Related Mortality in Older Men in a Prospective Cohort Study.

The effect of dietary salt intake on important population outcomes such as mortality is controversial. The aim of this study was to examine the association between the dietary habit of adding salt to food and mortality in older men. Design, participants, setting and measurements: A risk factor questionnaire which contained a question about the dietary habit of adding salt to food was completed by 11742 community recruited older men between 1996 and 1999. The men were followed by means of the Western Australia Data Linkage System until November 30th 2010. Deaths due to cardiovascular diseases and cancers were identified using ICD-10 codes in the ranges I00-I99 and C00-D48, respectively. The association between the frequencies of adding salt to food and mortality was assessed using Kaplan Meier estimates and Cox proportional hazard analysis. Median follow-up for survivors was 12.5 years (inter-quartile range 8.3-13.2 years). A total of 5399 deaths occurred of which the primary cause registered was cancer and cardiovascular disease in 1962 (36.3%) and 1835 (34.0%) men, respectively. The reported frequency of adding salt to food was strongly positively associated with all-cause (p<0.001), cancer-related (p<0.001) but not cardiovascular-related (p=0.649) mortality. Men reporting adding salt to their food always had a 1.12-fold (95% CI 1.05-1.20, p<0.001) and a 1.20-fold (95% CI 1.07-1.34, p=0.001) increased risk of all-cause and cancer-related mortality, respectively, after adjusting for other risk factors. Men reporting adding salt to their food sometimes had a 1.16-fold (95% CI 1.04-1.29, p=0.007) increased risk of cancer-related mortality after adjusting for other risk factors. A history of adding salt to food is associated with increased cancer-related mortality in older men.

Cardiovascular effects of dietary salt intake in aged healthy cats: a 2-year prospective randomized, blinded, and controlled study.

High salt dry expanded diets are commercially available for cats to increase water intake and urine volume, as part of the prevention or treatment of naturally occurring urinary stone formation (calcium oxalates and struvites). However, chronic high salt intake may have potential cardiovascular adverse effects in both humans, especially in aging individuals, and several animal models. The objective of this prospective, randomized, blinded, and controlled study was to assess the long-term cardiovascular effects of high salt intake in healthy aged cats. Twenty healthy neutered cats (10.1±2.4 years) were randomly allocated into 2 matched groups. One group was fed a high salt diet (3.1 g/Mcal sodium, 5.5 g/Mcal chloride) and the other group a control diet of same composition except for salt content (1.0 g/Mcal sodium, 2.2 g/Mcal chloride). Clinical examination, systolic and diastolic arterial blood pressure measurements, standard transthoracic echocardiography and conventional Doppler examinations were repeatedly performed on non-sedated cats by trained observers before and over 24 months after diet implementation. Radial and longitudinal velocities of the left ventricular free wall and the interventricular septum were also assessed in systole and diastole using 2-dimensional color tissue Doppler imaging. Statistics were performed using a general linear model. No significant effect of dietary salt intake was observed on systolic and diastolic arterial blood pressure values. Out of the 33 tested imaging variables, the only one affected by dietary salt intake was the radial early on late diastolic velocity ratio assessed in the endocardium of the left ventricular free wall, statistically lower in the high salt diet group at 12 months only (P = 0.044). In conclusion, in this study involving healthy aged cats, chronic high dietary salt intake was not associated with an increased risk of systemic arterial hypertension and myocardial dysfunction, as observed in some elderly people, salt-sensitive patients and animal models.

Effects of Dietary Salt Intake on Renal Function: A 2‐Year Study in Healthy Aged Cats

Increasing salt intake to promote diuresis has been suggested in the management of feline lower urinary tract disease. However, high dietary salt intake might adversely affect blood pressure and renal function. The objective of this study was to assess the long-term effects of increased salt intake on renal function in healthy aged cats. This study was controlled, randomized, and blinded. Twenty healthy neutered cats (10.1 ± 2.4 years) were randomly allocated into 2 matched groups. One group was fed a high salt diet (3.1 g/Mcal sodium, 5.5 g/Mcal chloride) and the other a control diet of same composition except for salt content (1.0 g/Mcal sodium, 2.2 g/Mcal chloride). Clinical examination, glomerular filtration rate, blood pressure measurement, cardiac and kidney ultrasonography, and urinary and blood tests were performed before and over 24 months after diet implementation. Statistics were performed using a general linear model. Sixteen cats completed the 2 year study. The only variables affected by dietary salt intake were plasma aldosterone and urinary sodium/creatinine ratio, respectively, higher and lower in the control group all over the study period and urinary specific gravity, lower in the high salt diet group at 3 months. Glomerular filtration rate (GFR), blood pressure, and other routine clinical pathological variables in healthy aged cats were not affected by dietary salt content. The results of this 2 year study do not support the suggestion that chronic increases in dietary salt intake are harmful to renal function in older cats.

Sodium challenge does not support an acute gastrointestinal–renal natriuretic signaling axis in humans

A gastrointestinal-renal natriuretic signaling axis has been proposed to regulate sodium excretion in response to acute sodium ingestion. Such an axis is thought to be regulated by a gastrointestinal sodium sensor coupled to the activation/release of a natriuretic signal and could have important clinical and scientific implications. Here we systematically tested for this putative axis and the potential involvement of the gastrointestinal-derived natriuretic prohormones prouroguanylin and proguanylin in 15 healthy volunteers. There was no difference in sodium excretion following equivalent oral or intravenous sodium loads during either high- or low-sodium diets. Furthermore, serum concentrations of prouroguanylin and proguanylin did not increase, did not differ following oral or intravenous sodium, and did not correlate with sodium excretion. Thus, our results do not support an acute gastrointestinal-renal natriuretic axis or a central role for prouroguanylin or proguanylin in humans. If such an axis does exist, it is not characterized by a significant difference in the pattern of sodium excretion following either an oral or intravenous sodium load.

Abstract 241: Influence of Dietary Salt and Renin-angiotensin System activity on plasma Retinol-binding Protein 4 in Healthy Human Subjects

Introduction: Retinol-binding protein 4 (RBP-4) is a circulating adipokine associated with insulin resistance, obesity and cardiovascular risk. Previous evidence suggests a negative impact on insulin sensitivity via an interaction with the insulin-stimulated glucose transporter (GLUT-4), specifically in adipocytes. Since angiotensin-2 (ANG-2) impairs GLUT-4 presentation and insulin sensitivity, we hypothesized that renin-angiotensin system (RAS) activity might affect RBP-4 expression as well. Furthermore, both RAS activity and insulin sensitivity are affected by dietary salt, but the relationship between these factors and RBP-4 expression is unknown. We hypothesized that liberal salt diet, via suppression of RAS activity, would be associated with reduced RBP-4 levels compared to salt restriction. METHODS: Healthy subjects (7 men, 7 women, mean age 24 yr, BMI 22.6) were studied on low salt (LS 10 mmol Na/day) diet and then liberal salt (HS 200 mmol Na/day) diet for 1 week each. Samples were drawn after overnight rest in the supine position for plasma renin activity (PRA), serum Aldosterone (Aldo) and plasma RBP-4 and again after ANG-2 infusion (3ng/kg/min x 45 mins). Results: Salt manipulation predictably modified RAS activity (HS v. LS Aldo, 4.5 ± 3.8 v. 19.5 ± 8.5 ng/dl [p&lt;0.01]; HS v. LS PRA, 0.5 ± 0.4 v. 2.7 ± 1.4 ng/ml/hr [p&lt;0.01]). RBP-4 was significantly lower on a HS compared to LS diet (35.4 ± 6.6 v. 38.6 ± 7.9 mg/L, p= 0.017). No significant change was observed in RBP-4 level after ANG-2 infusion on either diet. Fasting insulin levels trended lower on HS compared to LS (3.9 ± 6.8 v. 4.4 ± 1.2 μIU/ml, p=0.09), but there was no difference in fasting glucose (81.9 ± 6.8 v. 82.1 ± 4.7 mg/dl, p=0.92). Conclusion: RBP-4 levels are modified by dietary salt intake. RBP-4 levels were lower under HS conditions (suppressed RAS) as compared to LS conditions. Acute administration of ANG-2 does not increase RBP-4 levels in this healthy population. Insulin response was similar to prior reports suggesting that the connection between RAS activity, dietary salt and insulin sensitivity may include RBP-4. Future work exploring the relationship between RBP-4, GLUT-4 and insulin sensitivity should take into consideration the effect of dietary salt intake.

Polymorphisms in the serum- and glucocorticoid-inducible kinase 1 gene are associated with blood pressure and renin response to dietary salt intake

Serum- and glucocorticoid-inducible kinase 1 (SGK1) plays a central role in epithelial sodium channel (ENaC)-dependent Na+ transport in the distal nephron. We hypothesized that SGK1 gene variants may contribute to the effect of dietary salt intake on BP in humans with hypertension, and consequentially influence renin-angiotensin-aldosterone (RAA) system activity. Our study population included 421 hypertensive Caucasian participants of the HyperPath group who had completed a dietary salt protocol with measurement of BP and RAA system activity. Three SGK1 tagging single nucleotide polymorphisms (SNPs) from the HapMap CEU population captured the genetic variation in the SGK1 region. Assuming an additive genetic model, two SNPs (rs2758151 and rs9402571) were associated with BP and plasma renin activity (PRA) effects of dietary salt intake. Major alleles were associated with higher systolic BP on high salt and decreased PRA on low salt. In contrast, low salt neutralized genotype differences. Similar, non-significant trends were observed in a normotensive population (N=152). Genotype was also associated with two salt-sensitive subtypes of hypertension. SGK1 genetic variants are associated with salt sensitivity of BP and PRA in human hypertension. Genotype status at these SGK1 variants may identify individuals prone to salt-sensitive hypertension.

Activation of the Renin-Angiotensin System Mediates the Effects of Dietary Salt Intake on Atherogenesis in the Apolipoprotein E Knockout Mouse

Dietary salt intake is a major determinant of the activation state of renin-angiotensin-aldosterone system. Given the important role of the renin-angiotensin-aldosterone system in plaque accumulation, we investigated its role in the development of atherogenesis associated with sodium intake in apolipoprotein E knockout mice. Six-weeks of a low-salt diet (containing 0.03% sodium) resulted in a 4-fold increase in plaque accumulation in apolipoprotein E knockout mice when compared with mice receiving normal chow (containing 0.30% sodium). This was associated with activation of the renin-angiotensin-aldosterone system, increased vascular expression of adhesion molecules and inflammatory cytokines, and increased adhesion of labeled leukocytes across the whole aorta on a dynamic flow assay. These changes were blocked with the angiotensin-converting enzyme inhibitor perindopril (2 mg/kg per day). A high-salt diet (containing 3% sodium) attenuated vascular inflammation and atherogenesis, associated with suppression of the renin-angiotensin-aldosterone system, although systolic blood pressure levels were modestly increased (5 ± 1 mmHg). Constitutive activation of the renin-angiotensin-aldosterone system in angiotensin-converting enzyme 2 apolipoprotein E knockout mice was also associated with increased atherosclerosis and vascular adhesion, and this was attenuated by a high-salt diet associated with suppression of the renin-angiotensin-aldosterone system. By contrast, a low-salt diet failed to further activate the renin-angiotensin-aldosterone system or to increase atherosclerosis in angiotensin-converting enzyme 2 apolipoprotein E knockout mice. Together, these data validate a relationship between salt-mediated renin-angiotensin-aldosterone system activation and atherogenesis, which may partly explain the inconclusive or paradoxical findings of recent observational studies, despite clear effects on blood pressure.

Dietary salt loading impairs arterial vascular reactivity

Studies of sodium have shown improvements in vascular function and blood pressure (BP). The effect of chronic sodium loading from a low-sodium diet to a Western diet on vascular function and BP has been less well studied. The objective was to examine the effects of dietary salt intake on vascular function and BP. Thirty-five hypertensive volunteers met the inclusion criteria. After a 2-wk run-in with a low-sodium diet (60 mmol/d), the participants maintained their diets and were randomly assigned to receive sequentially 1 of 3 interventions for 4 wk, with a 2-wk washout between interventions: sodium-free tomato juice (A), tomato juice containing 90 mmol Na (B), and tomato juice containing 140 mmol Na (C). The outcomes were changes in pulse wave velocity (PWV), systolic BP (SBP), and diastolic BP (DBP). The difference in PWV between interventions B and A was 0.39 m/s (95% CI: 0.18, 0.60 m/s; P < or = 0.001) and between C and A was 0.35 m/s (95% CI: 0.13, 0.57 m/s; P < or = 0.01). Differences in SBP and DBP between interventions B and A were 4.4 mm Hg (95% CI: 1.2, 7.8 mm Hg; P < or = 0.01) and 2.4 mm Hg (95% CI: 0.8, 4.1 mm Hg; P < or = 0.001), respectively, and between interventions C and A were 5.6 mm Hg (95% CI: 2.7, 8.4 mm Hg; P < or = 0.01) and 3.3 mm Hg (95% CI: 1.5, 5.0 mm Hg; P < or = 0.001), respectively. Changes in PWV correlated with changes in SBP (r = 0.52) and DBP (r = 0.58). Dietary salt loading produced significant increases in PWV and BP in hypertensive volunteers. Correlations between BP and PWV suggest that salt loading may have a BP-independent effect on vascular wall function. This further supports the importance of dietary sodium restriction in the management of hypertension. This trial was registered with the Australian and New Zealand Clinical Trials Registry as ACTRN12609000161224.

Salt intake induces epithelial-to-mesenchymal transition of the peritoneal membrane in rats

Dietary salt intake has been linked to hypertension and cardiovascular disease through volume-mediated effects. Accumulating evidence points to direct negative influence of salt intake independent of volume overload, such as cardiac and renal fibrosis, mediated through transforming growth factor beta (TGF-beta). Epithelial-to-mesenchymal transition (EMT) has been implicated as a key process in chronic fibrotic diseases, such as chronic kidney disease or heart failure. The potential role of dietary salt intake on cell transdifferentiation has never been investigated. This study analysed the effect of dietary salt intake on EMT and fibrosis in the peritoneal membrane (PM) in a rat model. Twenty-eight Wistar rats were randomized to a normal salt (NS) or a high salt (HS) intake. NS and HS rats had free access to tap water or NaCl 2% as drinking water, respectively. After 2 weeks, samples of peritoneum were taken, and TGF-beta(1), Interleukin 6 (IL-6) and vascular endothelial growth factor (VEGF) mRNA expression were quantified with qRT-PCR. Fibrosis and submesothelial PM thickness were scored. EMT was evaluated using fluorescence staining with cytokeratin and alpha smooth muscle actin (alpha-SMA). Dietary salt intake caused peritoneal fibrosis and thickening of the submesothelial layer and induced EMT as identified by colocalization of cytokeratin and alpha-SMA in cells present in the submesothelial layer. Peritoneal TGF-beta(1) and IL-6 mRNA expression were upregulated in the HS group. High dietary salt intake induces EMT and peritoneal fibrosis, a process coinciding with upregulation of TGF-beta1.

Effect of dietary salt intake on circadian calcium metabolism, bone turnover, and calcium oxalate kidney stone risk in postmenopausal women

Increasing dietary salt (sodium chloride) increases urinary calcium excretion, which may increase the risk of developing osteoporosis and kidney stones. Ten postmenopausal women without osteoporosis or kidney stones who were not undergoing hormone replacement therapy ate all meals in a metabolic unit for 14 days: 7 days at each salt level in a crossover design. The 2 diets differed only by the addition of 150-mmol salt supplement to a 50-mmol baseline diet containing 780-mg calcium. Urinary calcium was higher in all 10 subjects taking the high-salt diet. Fasting calcitriol was not different. Comparing fasting with mid-morning, mid-afternoon, and evening samplings on day 7 of each diet, urinary deoxypyridinoline and N-telopeptide concentrations per mmol creatinine were higher in the evening on the high-salt diet. Fasting and postdinner osteocalcin values were higher on the low-salt diet. Ionized calcium, mid-molecule parathyroid hormone, and bone alkaline phosphatase were not different at any time point. Urinary volume, calcium, and oxalate but not magnesium, citrate, and the calculated calcium oxalate kidney stone risk index were higher on the high-salt diet. High dietary salt intakes by non–stone-forming postmenopausal women not taking estrogen may increase the risk of developing osteoporosis but not that of calcium oxalate kidney stones.