Sodium Intake and Heart Failure.

Sodium is an essential mineral and nutrient used in dietary practices across the world and is important to maintain proper blood volume and blood pressure. A high sodium diet is associated with increased expression of ß-myosin heavy chain, decreased expression of α/ß-myosin heavy chain, increased myocyte enhancer factor 2/nuclear factor of activated T cell transcriptional activity, and increased salt-inducible kinase 1 expression, which leads to alteration in myocardial mechanical performance. A high sodium diet is also associated with alterations in various proteins responsible for calcium homeostasis and myocardial contractility. Excessive sodium intake is associated with the development of a variety of comorbidities including hypertension, chronic kidney disease, stroke, and cardiovascular diseases. While the American College of Cardiology/American Heart Association/Heart Failure Society of America guidelines recommend limiting sodium intake to both prevent and manage heart failure, the evidence behind such recommendations is unclear. Our review article highlights evidence and underlying mechanisms favoring and contradicting limiting sodium intake in heart failure.

Diabetes Mellitus and Hypertension-A Case of Sugar and Salt?

The majority of patients with diabetes mellitus (DM) have hypertension (HTN). A specific mechanism for the development of HTN in DM has not been described. In the Zucker, Endothel, und Salz (sugar, endothelium, and salt) study (ZEuS), indices of glucose metabolism and of volume regulation are recorded. An analysis of these parameters shows that glucose concentrations interfere with plasma osmolality and that changes in glycemic control have a significant impact on fluid status and blood pressure. The results of this study are discussed against the background of the striking similarities between the regulation of sugar and salt blood concentrations, introducing the view that DM is probably a sodium-retention disorder that leads to a state of hypervolemia.

The Impact of High Dietary Sodium Consumption on Blood Pressure Variability in Healthy, Young Adults.

BACKGROUND: High sodium (Na+) intake augments blood pressure variability (BPV) in normotensive rodents, without changes in resting blood pressure (BP). Augmented BPV is associated with end-organ damage and cardiovascular morbidity. It is unknown if changes in dietary Na+ influence BPV in humans. We tested the hypothesis that high Na+ feeding would augment BPV in healthy adults. METHODS: Twenty-one participants (10 F/11 M; 26 ± 5 years; BP: 113 ± 11/62 ± 7 mm Hg) underwent a randomized, controlled feeding study that consisted of 10 days of low (2.6 g/day), medium (6.0 g/day), and high (18.0 g/day) salt diets. On the ninth day of each diet, 24-h urine samples were collected and BPV was calculated from 24-h ambulatory BP monitoring. On the tenth day, in-laboratory beat-to-beat BPV was calculated during 10 min of rest. Serum electrolytes were assessed. We calculated average real variability (ARV) and standard deviation (SD) as metrics of BPV. As a secondary analysis, we calculated central BPV from the 24-h ambulatory BP monitoring. RESULTS: 24-h urinary Na+ excretion (low = 41 ± 24, medium = 97 ± 43, high = 265 ± 92 mmol/24 h, P < 0.01) and serum Na+ (low = 140.0 ± 2.1, medium = 140.7 ± 2.7, high = 141.7 ± 2.5 mmol/l, P = 0.009) increased with greater salt intake. 24-h ambulatory ARV (systolic BP ARV: low = 9.5 ± 1.7, medium = 9.5 ± 1.2, high = 10.0 ± 1.9 mm Hg, P = 0.37) and beat-to-beat ARV (systolic BP ARV: low = 2.1 ± 0.6, medium = 2.0 ± 0.4, high = 2.2 ± 0.8 mm Hg, P = 0.46) were not different. 24-h ambulatory SD (systolic BP: P = 0.29) and beat-to-beat SD (systolic BP: P = 0.47) were not different. There was a trend for a main effect of the diet (P = 0.08) for 24-h ambulatory central systolic BPV. CONCLUSIONS: Ten days of high sodium feeding does not augment peripheral BPV in healthy, adults. CLINICAL TRIALS REGISTRATION: NCT02881515.

Effects of mandatory salt iodization on breast milk, urinary iodine concentrations, and thyroid hormones: is iodine deficiency still a continuing problem?

PURPOSE: To investigate whether mandatory use of iodized salt in Turkey, since 1999 has sufficient effects on pregnant women and their newborns' urinary iodine concentrations (UIC), maternal and newborns' thyroid function tests and breast milk iodine concentrations (BMIC). METHODS: This cross-sectional analytical-type study was conducted in an obstetrics and gynecology hospital in Konya, Turkey. One hundred and seven pregnant women and their 107 full-term newborns were included into the study. Levels of pregnant women and their newborns' UIC, thyroid-stimulated hormone (TSH), free triiodothyronine (fT3), free thyroxine (fT4), thyroglobulin (Tg), and BMIC were studied. RESULTS: Of 107 women with term pregnancy, mean TSH value and hypothyroidism frequency were found as 2.34 ± 1.33 mIU/L and 18.7%, respectively. Cord blood TSH level was found higher (≥ 10 mIU/L) in five newborns. Accordingly, the incidence of transient congenital hypothyroidism was 4.7% (5/107). Tg levels were observed to be higher in 50.5% of newborns and 22.4% of pregnant women. Frequency of iodized salt use in pregnancies was detected as 96.3% in general population, 97.5% in urban, and 92.9% in rural areas. Of pregnancies and newborns, 57.9 and 53.3% were found to have deficient urinary iodine, respectively, and BMIC deficiency was detected as 52.0%. There was a significant positive correlation between pregnant women's UIC, and newborns' UIC and BMIC. CONCLUSIONS: Despite the effective struggle with iodine deficiency and salt iodination control program in Konya, we concluded that iodine deficiency still persists as a significant problem in pregnancies.

High-salt diet affects amino acid metabolism in plasma and muscle of Dahl salt-sensitive rats.

Genetic background and high-salt diet are considered key factors contributing to the development of hypertension and its associated metabolic disorders. Metabolomics is an emerging powerful tool to analyze the low-molecular weight metabolites in plasma and tissue. This study integrated metabolomics and correlation network analysis to investigate the metabolic profiles of plasma and muscle of Dahl salt-sensitive (SS) rats and SS.13BN rats (control) under normal and high-salt diet. The hub metabolites, which could play important roles in the metabolic changes, were identified by correlation network analysis. The results of the network analysis were further confirmed by pathway analysis and enzyme activity analysis. The results indicated a higher amino acid levels in both plasma and muscle of SS rats fed with high-salt diet. Alanine was found as a hub metabolite with the highest score of three centrality indices and also as the significant differential metabolite in plasma of SS rats after high-salt diet. Valine and lysine were found as hub metabolites and differential metabolites in muscle of SS rats after high-salt diet. Amino acid levels increased in both plasma and muscle of SS rats fed with a high salt diet. Moreover, alanine in plasma and valine and lysine in muscle as hub metabolites could play important roles in the response to high-salt diet.

Alterations in dietary sodium intake affect cardiovagal baroreflex sensitivity.

High dietary sodium intake has been linked to alterations in neurally mediated cardiovascular function, but the effects of high sodium on cardiovagal baroreflex sensitivity (cBRS) in healthy adults are unknown. The purpose of this study was to determine whether high dietary sodium alters cBRS and heart rate variability (HRV) and whether acute intravenous sodium loading similarly alters cBRS and HRV. High dietary sodium (300 mmol/day, 7 days) was compared with low dietary sodium (20 mmol/day, 7 days; randomized) in 14 participants (38 ± 4 yr old, 23 ± 1 kg/m2 body mass index, 7 women). Acute sodium loading was achieved via a 23-min intravenous hypertonic saline infusion (HSI) in 14 participants (22 ± 1 yr old, 23 ± 1 kg/m2 body mass index, 7 women). During both protocols, participants were supine for 5 min during measurement of beat-to-beat blood pressure (photoplethysmography) and R-R interval (ECG). cBRS was evaluated using the sequence method. Root mean square of successive differences in R-R interval (RMSSD) was used as an index of HRV. Serum sodium (137.4 ± 0.7 vs. 139.9 ± 0.5 meq/l, P < 0.05), plasma osmolality (285 ± 1 vs. 289 ± 1 mosmol/kgH2O, P < 0.05), cBRS (18 ± 2 vs. 26 ± 3 ms/mmHg, P < 0.05), and RMSSD (62 ± 6 vs. 79 ± 10 ms, P < 0.05) were increased following high-sodium diet intake compared with low-sodium diet intake. HSI increased serum sodium (138.1 ± 0.4 vs. 141.1 ± 0.5 meq/l, P < 0.05) and plasma osmolality (286 ± 1 vs. 290 ± 1 mosmol/kgH2O, P < 0.05) but did not change cBRS (26 ± 5 vs. 25 ± 3 ms/mmHg, P = 0.73) and RMSSD (63 ± 9 vs. 63 ± 8 ms, P = 0.99). These data suggest that alterations in dietary sodium intake alter cBRS and HRV but that acute intravenous sodium loading does not alter these indexes of autonomic cardiovascular regulation.

Effect of Salt Intervention on Serum Levels of Fibroblast Growth Factor 23 (FGF23) in Chinese Adults: An Intervention Study.

BACKGROUND Fibroblast growth factor 23 (FGF23), a prominent regulator of phosphate and calcium metabolism, regulates sodium excretion in distal tubules through sodium-chloride cotransporter. This effect regulates blood pressure. Salt intake exerts effects on serum levels of FGF23 in mice. The aim of this study was to explore whether salt intervention affects serum concentrations of FGF23 in Chinese adults. MATERIAL AND METHODS We enrolled 44 participants from Lantian, a rural community of Shaanxi, China. All participants were maintained on a three-day normal diet, which was sequentially followed by a seven-day low-Na+ diet and seven-day high-Na+ diet. Serum FGF23 concentrations were assessed by ELISA. RESULTS Serum FGF23 concentrations elevated during low-salt diet compared with levels at baseline (66.20±44.21 pg/mL versus 86.77±53.74 pg/mL, p<0.05) and remarkably decreased when changed from low to high salt intake (86.77±53.74 pg/mL versus 49.26±42.67 pg/mL, p<0.001). Responses of FGF23 to salt intervention were more prominent in normotensive, older than 60 years, BMI <24 kg/m² and salt-resistant individuals. Furthermore, a significant inverse correlation was observed between 24-hour urinary sodium and serum concentrations of FGF23 after adjusting age, sex, BMI and hypertension status. CONCLUSIONS Dietary salt intervention significantly affects serum FGF23 in Chinese adults.

Effects of reducing processed culinary ingredients and ultra-processed foods in the Brazilian diet: a cardiovascular modelling study.

OBJECTIVE: To estimate the impact of reducing saturated fat, trans-fat, salt and added sugar from processed culinary ingredients and ultra-processed foods in the Brazilian diet on preventing cardiovascular deaths by 2030. DESIGN: A modelling study. SETTING: Data were obtained from the Brazilian Household Budget Survey 2008/2009. All food items purchased were categorized into food groups according to the NOVA classification. We estimated the energy and nutrient profile of foods then used the IMPACT Food Policy model to estimate the reduction in deaths from CVD up to 2030 in three scenarios. In Scenario A, we assumed that the intakes of saturated fat, trans-fat, salt and added sugar from ultra-processed foods and processed culinary ingredients were reduced by a quarter. In Scenario B, we assumed a reduction of 50 % of the same nutrients in ultra-processed foods and processed culinary ingredients. In Scenario C, we reduced the same nutrients in ultra-processed foods by 75 % and in processed culinary ingredients by 50 %. RESULTS: Approximately 390 400 CVD deaths might be expected in 2030 if current mortality patterns persist. Under Scenarios A, B and C, CVD mortality can be reduced by 5·5, 11·0 and 29·0 %, respectively. The main impact is on stroke with a reduction of approximately 6·0, 12·6 and 32·0 %, respectively. CONCLUSIONS: Substantial potential exists for reducing the CVD burden through overall improvements of the Brazilian diet. This might require reducing the penetration of ultra-processed foods by means of regulatory policies, as well as improving the access to and promotion of fresh and minimally processed foods.

Salt-dependent Blood Pressure in Human Aldosterone Synthase-Transgenic Mice.

Hypertension is one of the most important, preventable causes of premature morbidity and mortality in the developed world. Aldosterone is a major mineralocorticoid hormone that plays a key role in the regulation of blood pressure and is implicated in the pathogenesis of hypertension and heart failure. Aldosterone synthase (AS, cytochrome P450 11B2, cyp11B2) is the sole enzyme responsible for the production of aldosterone in humans. To determine the effects of increased expression of human aldosterone synthase (hAS) on blood pressure (BP), we established transgenic mice carrying the hAS gene (cyp11B2). We showed that hAS overexpression increased levels of aldosterone in hAS+/- mice. On high salt diet (HS), BPs of hAS+/- mice were significantly increased compared with WT mice. Fadrozole (an inhibitor of aldosterone synthase) treatment significantly reduced BPs of hAS+/- mice on HS. This is the first time overexpression of AS in a transgenic mouse line has shown an ability to induce HP. Specifically inhibiting AS activity in these mice is a promising therapy for reducing hypertension. This hAS transgenic mouse model is therefore an ideal animal model for hypertension therapy studies.

Hydrogen sulfide in paraventricular nucleus attenuates blood pressure by regulating oxidative stress and inflammatory cytokines in high salt-induced hypertension.

Hydrogen sulfide (H2S) is an important gaseous signaling molecule in neuro-modulation, anti-inflammatory, anti-oxidant and anti-hypertensive effects. The paraventricular nucleus (PVN) is a major integrative nucleus in regulating BP and SNA. The aim of this study is to explore whether endogenous or exogenous H2S changed by hydroxylamine hydrochloride (HA) or GYY4137 infused in the PVN affects RSNA and MAP by regulating oxidative stress or the balance between pro-inflammatory cytokines (PICs) and anti-inflammatory cytokines in high salt-induced hypertensive rats. Male Dahl rats were fed by high-salt or normal-salt diet. At the end of the 4th week, GYY4137, HA or vehicle was microinjected into bilateral PVN for 6 weeks. The levels of MAP, HR, plasma norepinephrine (NE), reactive oxygen species (ROS), NOX2, NOX4 and IL-1ß were increased significantly in high salt-induced hypertensive rats. Higher levels of these parameters were detected in the group treated by HA, but lower levels in the GYY4137 group. The trends of H2S, CBS, IL-10 and Cu/Zn SOD were opposite to the parameters described above. These findings suggest that endogenous or exogenous H2S in the PVN attenuates sympathetic activity and hypertensive response, which are partly due to decrease of ROS and PICs within the PVN in high salt-induced hypertension.

Blood pressure and sodium: Association with MRI markers in cerebral small vessel disease.

Dietary salt intake and hypertension are associated with increased risk of cardiovascular disease including stroke. We aimed to explore the influence of these factors, together with plasma sodium concentration, in cerebral small vessel disease (SVD). In all, 264 patients with nondisabling cortical or lacunar stroke were recruited. Patients were questioned about their salt intake and plasma sodium concentration was measured; brain tissue volume and white-matter hyperintensity (WMH) load were measured using structural magnetic resonance imaging (MRI) while diffusion tensor MRI and dynamic contrast-enhanced MRI were acquired to assess underlying tissue integrity. An index of added salt intake (P = 0.021), pulse pressure (P = 0.036), and diagnosis of hypertension (P = 0.0093) were positively associated with increased WMH, while plasma sodium concentration was associated with brain volume (P = 0.019) but not with WMH volume. These results are consistent with previous findings that raised blood pressure is associated with WMH burden and raise the possibility of an independent role for dietary salt in the development of cerebral SVD.

Norepinephrine-evoked salt-sensitive hypertension requires impaired renal sodium chloride cotransporter activity in Sprague-Dawley rats.

Recent studies have implicated a role of norepinephrine (NE) in the activation of the sodium chloride cotransporter (NCC) to drive the development of salt-sensitive hypertension. However, the interaction between NE and increased salt intake on blood pressure remains to be fully elucidated. This study examined the impact of a continuous NE infusion on sodium homeostasis and blood pressure in conscious Sprague-Dawley rats challenged with a normal (NS; 0.6% NaCl) or high-salt (HS; 8% NaCl) diet for 14 days. Naïve and saline-infused Sprague-Dawley rats remained normotensive when placed on HS and exhibited dietary sodium-evoked suppression of peak natriuresis to hydrochlorothiazide. NE infusion resulted in the development of hypertension, which was exacerbated by HS, demonstrating the development of the salt sensitivity of blood pressure [MAP (mmHg) NE+NS: 151 ± 3 vs. NE+HS: 172 ± 4; P < 0.05]. In these salt-sensitive animals, increased NE prevented dietary sodium-evoked suppression of peak natriuresis to hydrochlorothiazide, suggesting impaired NCC activity contributes to the development of salt sensitivity [peak natriuresis to hydrochlorothiazide (µeq/min) Naïve+NS: 9.4 ± 0.2 vs. Naïve+HS: 7 ± 0.1; P < 0.05; NE+NS: 11.1 ± 1.1; NE+HS: 10.8 ± 0.4). NE infusion did not alter NCC expression in animals maintained on NS; however, dietary sodium-evoked suppression of NCC expression was prevented in animals challenged with NE. Chronic NCC antagonism abolished the salt-sensitive component of NE-mediated hypertension, while chronic ANG II type 1 receptor antagonism significantly attenuated NE-evoked hypertension without restoring NCC function. These data demonstrate that increased levels of NE prevent dietary sodium-evoked suppression of the NCC, via an ANG II-independent mechanism, to stimulate the development of salt-sensitive hypertension.

Fluid deprivation increases isotonic NaCl intake, but not hypertonic salt intake, under normal and heated conditions in obese Zucker rats.

In the course of exposure to fluid deprivation and heated environment, mammals regulate their hydromineral balance and body temperature by a number of mechanisms including sweating, water and salt intakes. Here we challenged obese Zucker rats, known to have a predisposition to hypertension, with 0.9%NaCl alone or with 2%NaCl solution + water to drink under fluid deprivation and heated conditions. Food and fluid intakes, body weight, diuresis and natriuresis were measured daily throughout. Serum aldosterone levels and Na(+) concentration were also analyzed. Data showed that obese and lean rats presented similar baseline measurements of food, 0.9%NaCl and fluid intakes, diuresis and fluid balance; whereas hypertonic 2%NaCl consumption was almost absent. Before and during fluid deprivation animals increased isotonic but not hypertonic NaCl intake; the obese showed significant increases in diuresis and Na(+) excretion, whereas, total fluid intake was similar between groups. Heat increased isotonic NaCl intake and doubled natriuresis in obese which were wet on their fur and displayed a paradoxical increase of fluid gain. Fluid deprivation plus heat produced similar negative fluid balance in all groups. Body weight losses, food intake and diuresis reductions were amplified under the combined conditions. Animals exposed to 2%NaCl showed higher circulating levels of aldosterone and obese were lower than leans. In animals which drank 0.9%NaCl, obese showed higher serum levels of Na(+) than leans. We conclude that in spite of their higher sensitivity to high salt and heat obese Zucker rats can control hydromineral balance in response to fluid deprivation and heat by adjusting isotonic NaCl preference with sodium balance and circulating levels of aldosterone. This suggests a key hormonal role in the mechanisms underlying thermoregulation, body fluid homeostasis and sodium intake.

Fibroblast growth factor 23 and the antiproteinuric response to dietary sodium restriction during renin-angiotensin-aldosterone system blockade.

BACKGROUND: Residual proteinuria during renin-angiotensin-aldosterone system (RAAS) blockade is a major renal and cardiovascular risk factor in chronic kidney disease. Dietary sodium restriction potentiates the antiproteinuric effect of RAAS blockade, but residual proteinuria remains in many patients. Previous studies linked high fibroblast growth factor 23 (FGF-23) levels with volume overload; others linked higher serum phosphate levels with impaired RAAS-blockade efficacy. We hypothesized that FGF-23 reduces the capacity of dietary sodium restriction to potentiate RAAS blockade, impairing the antiproteinuric effect. STUDY DESIGN: Post hoc analysis of cohort data from a randomized crossover trial with two 6-week study periods comparing proteinuria after a regular-sodium diet with proteinuria after a low-sodium diet, both during background angiotensin-converting enzyme inhibition. SETTING & PARTICIPANTS: 47 nondiabetic patients with CKD with residual proteinuria (median protein excretion, 1.9 [IQR, 0.8-3.1] g/d; mean age, 50±13 [SD] years; creatinine clearance, 69 [IQR, 50-110] mL/min). PREDICTOR: Plasma carboxy-terminal FGF-23 levels. OUTCOMES: Difference in residual proteinuria at the end of the regular-sodium versus low-sodium study period. Residual proteinuria during the low-sodium diet period adjusted for proteinuria during the regular-sodium diet period. RESULTS: Higher baseline FGF-23 level was associated with reduced antiproteinuric response to dietary sodium restriction (standardized ß=-0.46; P=0.001; model R(2)=0.71). For every 100-RU/mL increase in FGF-23 level, the antiproteinuric response to dietary sodium restriction was reduced by 10.6%. Higher baseline FGF-23 level was a determinant of more residual proteinuria during the low-sodium diet (standardized ß=0.27; P=0.003) in linear regression analysis adjusted for baseline proteinuria (model R(2)=0.71). There was no interaction with creatinine clearance (P interaction=0.5). Baseline FGF-23 level did not predict changes in systolic or diastolic blood pressure upon intensified antiproteinuric treatment. LIMITATIONS: Observational study, limited sample size. CONCLUSIONS: FGF-23 levels are associated independently with impaired antiproteinuric response to sodium restriction in addition to RAAS blockade. Future studies should address whether FGF-23-lowering strategies may further optimize proteinuria reduction by RAAS blockade combined with dietary sodium restriction.

An efficacy study on alleviating micronutrient deficiencies through a multiple micronutrient fortified salt in children in South India.

BACKGROUND: Multiple micronutrient deficiencies are prevalent in India. OBJECTIVE: The study aims to establish the efficacy of multi-micronutrient fortified salt in addressing multiple micronutrient deficiencies among children compared to nutrition education and no intervention in Tamilnadu. METHODS: The study employed a community based randomized controlled trial designed to study the impact of multiple micronutrient salt (micronutrient group) in comparison with nutrition education (education group) and no intervention (control group) on haemoglobin, serum ferritin, soluble transferrin receptor, body iron stores, serum retinol and urinary iodine outcomes over a period of 8 months. The fortified salt contained iron, iodine, vitamin A, vitamin B12 and folic acid. All the children were dewormed at baseline and at the end of the study just before the biochemical measurements. RESULTS: There was a significant improvement in most biochemical parameters studied in the micronutrient group when compared with the control group whereas this was not seen between the education and control. Over 8 months, in the micronutrient group, hemoglobin increased by 0.52 g/dL, retinol by 8.56 µg/dL, ferritin by 10.8 µg/L, body iron stores by 1.27 mg and the decrease in the prevalence of retinol deficiency was from 51.6% to 28.1%, anaemia from 46.0% to 32.6%, iron deficiency from 66.9% to 51.3% and iron deficiency anaemia from 35.2% to 31.0%, while the prevalence of all these deficiencies increased or the changes were not significant in the other two groups. CONCLUSIONS: Multiple micronutrient fortified salt was able to improve iron and vitamin A status, whereas this was not seen in the nutrition education group.

Analysis of metabolites in plasma reveals distinct metabolic features between Dahl salt-sensitive rats and consomic SS.13(BN) rats.

Salt-sensitive hypertension is a major risk factor for cardiovascular disorders. Our previous proteomic study revealed substantial differences in several proteins between Dahl salt-sensitive (SS) rats and salt-insensitive consomic SS.13(BN) rats. Subsequent experiments indicated a role of fumarase insufficiency in the development of hypertension in SS rats. In the present study, a global metabolic profiling study was performed using gas chromatography/mass spectrometry (GC/MS) in plasma of SS rats (n=9) and SS.13(BN) rats (n=8) on 0.4% NaCl diet, designed to gain further insights into the relationship between alterations in cellular intermediary metabolism and predisposition to hypertension. Principal component analysis of the data sets revealed a clear clustering and separation of metabolic profiles between SS rats and SS.13(BN) rats. 23 differential metabolites were identified (P<0.05). Higher levels of five TCA cycle metabolites, fumarate, cis-aconitate, isocitrate, citrate and succinate, were observed in SS rats. Pyruvate, which connects TCA cycle and glycolysis, was also increased in SS rats. Moreover, lower activity levels of fumarase, aconitase, α-ketoglutarate dehydrogenase and succinyl-CoA synthetase were detected in the heart, liver or skeletal muscles of SS rats. The distinct metabolic features in SS and SS.13(BN) rats indicate abnormalities of TCA cycle in SS rats, which may play a role in predisposing SS rats to developing salt-sensitive hypertension.

5-HT neurons of the area postrema become c-Fos-activated after increases in plasma sodium levels and transmit interoceptive information to the nucleus accumbens.

Serotonergic (5-hydroxytryptamine, 5-HT) neurons of the area postrema (AP) represent one neuronal phenotype implicated in the regulation of salt appetite. Tryptophan hydroxylase (Tryp-OH, synthetic enzyme-producing 5-HT) immunoreactive neurons in the AP of rats become c-Fos-activated following conditions in which plasma sodium levels are elevated; these include intraperitoneal injections of hypertonic saline and sodium repletion. Non-Tryp-OH neurons also became c-Fos-activated. Sodium depletion, which induced an increase in plasma osmolality but caused no significant change in the plasma sodium concentration, had no effect on the c-Fos activity in the AP. Epithelial sodium channels are expressed in the Tryp-OH-immunoreactive AP neurons, possibly functioning in the detection of changes in plasma sodium levels. Since little is known about the neural circuitry of these neurons, we tested whether the AP contributes to a central pathway that innervates the reward center of the brain. Stereotaxic injections of pseudorabies virus were made in the nucleus accumbens (NAc), and after 4 days, this viral tracer produced retrograde transneuronal labeling in the Tryp-OH and non-Tryp-OH AP neurons. Both sets of neurons innervate the NAc via a multisynaptic pathway. Besides sensory information regarding plasma sodium levels, the AP→NAc pathway may also transmit other types of chemosensory information, such as those related to metabolic functions, food intake, and immune system to the subcortical structures of the reward system. Because these subcortical regions ultimately project to the medial prefrontal cortex, different types of chemical signals from visceral systems may influence affective functions.

Mice carrying ubiquitin-specific protease 2 (Usp2) gene inactivation maintain normal sodium balance and blood pressure.

Ubiquitylation plays an important role in the control of Na⁺ homeostasis by the kidney. It is well established that the epithelial Na⁺ channel ENaC is regulated by the ubiquitin-protein ligase NEDD4-2, limiting ENaC cell surface expression and activity. Ubiquitylation can be reversed by the action of deubiquitylating enzymes (DUBs). One such DUB, USP2-45, was identified previously as an aldosterone-induced protein in the kidney and is also a circadian output gene. In heterologous expression systems, USP2-45 binds to ENaC, deubiquitylates it, and enhances channel density and activity at the cell surface. Because the role of USP2-45 in renal Na⁺ transport had not been studied in vivo, we investigated here the effect of Usp2 gene inactivation in this process. We demonstrate first that USP2-45 protein has a rhythmic expression with a peak at ZT12. Usp2-KO mice did not show any differences from wild-type littermates with respect to the diurnal control of Na⁺ or K⁺ urinary excretion and plasma levels either on a standard diet or after acute and chronic changes to low- and high-Na⁺ diets, respectively. Moreover, they had similar aldosterone levels on either a low- or high-Na⁺ diet. Blood pressure measurements using telemetry did not reveal variations compared with control mice. Usp2-KO mice did not display alterations in expression of genes involved in sodium homeostasis or the ubiquitin system, as evidenced by transcriptome analysis in the kidney. Our data suggest that USP2 does not play a primary role in the control of Na⁺ balance or blood pressure.

Sodium- and phosphorus-based food additives: persistent but surmountable hurdles in the management of nutrition in chronic kidney disease.

Sodium- and phosphorus-based food additives are among the most commonly consumed nutrients in the world. This is because both have diverse applications in processed food manufacturing, leading to their widespread use by the food industry. Since most foods are naturally low in salt, sodium additives almost completely account for the excessive consumption of sodium throughout the world. Similarly, phosphorus additives represent a major and "hidden" phosphorus load in modern diets. These factors pose a major barrier to successfully lowering sodium or phosphorus intake in patients with CKD. As such, any serious effort to reduce sodium or phosphorus consumption will require reductions in the use of these additives by the food industry. The current regulatory environment governing the use of food additives does not favor this goal, however, in large part because these additives have historically been classified as generally safe for public consumption. To overcome these barriers, coordinated efforts will be needed to demonstrate that high intake of these additives is not safe for public consumption and as such should be subject to greater regulatory scrutiny.