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We have recently reported that the urea osmolyte-associated water conservation system is activated in fluid loss models such as high salt-induced natriuresis, renal injury-induced impaired renal concentrating ability, or skin barrier dysfunction-induced transepidermal water loss. The system consists of the interaction of multiple organs including renal urea recycling, hepato-muscular ureagenesis, and suppression of cardiovascular energy expenditure. Here, we determined the effect of pharmacological fluid loss induced by tolvaptan, a selective vasopressin V

Chronic renal failure leads to muscle mass loss and hypertension, which according to textbook teaching occur secondary to an inability of the kidneys to excrete solutes and water. We found instead that rats with experimental chronic renal failure constantly lost body water, because their kidneys could not sufficiently concentrate the urine. Physiological adaptation to body water loss, termed aestivation, is an evolutionary conserved survival strategy that relies on complex physiologic-metabolic adjustment across multiple organs to prevent otherwise lethal dehydration. We show that rats with chronic renal failure utilize these ancient water conservation motifs to successfully stabilize their body water. Metabolic aestivation responses to chronic renal failure require nitrogen-rich organic osmolyte production. Continuous endogenous energy and nitrogen supply from skeletal muscle in support of this metabolic requirement explains “renal” muscle mass loss. Accompanying circulatory aestivation responses are designed to limit skin water loss. This process requires vasoconstriction, which explains “renal” hypertension.

Long-term elevated blood sugar levels result in tissue matrix compositional changes in patients with diabetes mellitus type 2 (T2DM). We hypothesized that hemodialysis patients with T2DM might accumulate more tissue sodium than control hemodialysis patients. To test this, 23Na magnetic resonance imaging (23Na MRI) was used to estimate sodium in skin and muscle tissue in hemodialysis patients with or without T2DM. Muscle fat content was estimated by 1H MRI and tissue sodium content by 23Na MRI pre- and post-hemodialysis in ten hemodialysis patients with T2DM and in 30 matched control hemodialysis patients. We also assessed body fluid distribution with the Body Composition Monitor. 1H MRI indicated a tendency to higher muscle fat content in hemodialysis patients with T2DM compared to non-diabetic hemodialysis patients. 23Na MRI indicated increased sodium content in muscle and skin tissue of hemodialysis patients with T2DM compared to control hemodialysis patients. Multi-frequency bioimpedance was used to estimate extracellular water (ECW), and excess ECW in T2DM hemodialysis patients correlated with HbA1c levels. Sodium mobilization during hemodialysis lowered muscle sodium content post-dialysis to a greater degree in T2DM hemodialysis patients than in control hemodialysis patients. Thus, our findings provide evidence that increased sodium accumulation occurs in hemodialysis patients with T2DM and that impaired serum glucose metabolism is associated with disturbances in tissue sodium and water content.

SUMMARY 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., In Brief Barbaro et al. describe a pathway by which increased extracellular sodium activates dendritic cells. This pathway potentially explains the link between excessive salt intake, inflammation, and high blood pressure.

Rationale and Objectives Sodium and proton magnetic resonance imaging (23Na/1H-MRI) have shown that muscle and skin can store Na+ without water. In chronic renal failure and in heart failure, Na+ mobilization occurs, but is variable depending on age, dialysis vintage, and other features. Na+ storage depots have not been studied in patients with acute kidney injury (AKI). Materials and Methods We studied 7 patients with AKI (mean age: 51.7 years; range: 25–84) and 14 age-matched and gender-matched healthy controls. All underwent 23Na/1H-MRI at the calf. Patients were studied before and after acute hemodialysis therapy within 5–6 days. The 23Na-MRI produced grayscale images containing Na+ phantoms, which served to quantify Na+ contents. A fat-suppressed inversion recovery sequence was used to quantify H2O content. Results Plasma Na+ levels did not change. Mean Na+ contents in muscle and skin did not significantly change following four to five cycles of hemodialysis treatment (before therapy: 32.7 ± 6.9 and 44.2 ± 13.5 mmol/L, respectively; after dialysis: 31.7 ± 10.2 and 42.8 ± 11.8 mmol/L, respectively; P > .05). Water content measurements did not differ significantly before and after hemodialysis in muscle and skin (P > .05). Na+ contents in calf muscle and skin of patients before hemodialysis were significantly higher than in healthy subjects (16.6 ± 2.1 and 17.9 ± 3.2) and remained significantly elevated after hemodialysis. Conclusions Na+ in muscle and skin accumulates in patients with AKI and, in contrast to patients receiving chronic hemodialysis and those with acute heart failure, is not mobilized with hemodialysis within 5–6 days.

Blood pressure salt sensitivity and salt resistance are mechanistically imperfectly explained. A prescient systems medicine approach by Guyton and colleagues—more than 50 years ago—suggested how salt intake might influence blood pressure. They proposed that a high-salt diet engenders sodium accumulation, volume expansion, cardiac output adjustments, and then autoregulation for flow maintenance. The autoregulation in all vascular beds increases systemic vascular resistance, causing the kidneys to excrete more salt and water, thus reducing systems to normal and minimizing any changes in blood pressure. This schema, which is remarkably all encompassing, included all regulatory mechanisms Guyton could identify at the time. Guyton introduced the idea that the kidney is central, particularly concerning the regulation of renal pressure natriuresis. Numerous criticisms have been subsequently raised, particularly recently. Kurtz and colleagues argue that the ability of individuals to respond with an appropriate vasodilatory response to increased salt intake is pivotal. Data exist to address that issue. Salt-resistant hypertensive models provide additional information. We identified a mendelian form of hypertension not related to sodium reabsorption in the distal nephron. The hypertension develops because of increased systemic vascular resistance. In addition, we rediscovered a third salt-storage glycose-aminoglycan–related compartment, largely in the skin. This compartment operates independently of renal function, and when perturbed, is associated with salt sensitivity. More recently, we found novel molecular mechanisms demonstrating how large salt quantities are excreted by the kidneys with minimal water losses. We introduce novel interpretations as to how the kidneys excrete salt when the intake is high. The findings could have relevance as to how blood pressure may be regulated at varying salt intakes. Our purposes are to provide the readership with a banquet of thoughts to digest, to pursue Guyton's ideas, and to adjust them accordingly.

The aim of this work was to investigate possible sex differences in the patterns of sodium deposition between muscle and skin using sodium MRI. A total of 38 subjects were examined for comparisons: 20 males, aged 2579 years with a median age of 51; 18 females, aged 38-66 years, median age 53. All subjects underwent sodium MRI scans of the calf muscles together with cross sections through four calibration standards containing known sodium contents (10 mM, 20 mM, 30 mM, and 40 mM). Tissue sodium concentrations (TSC) in muscle and skin were then calculated by comparing signal intensities between tissues and reference standards using a linear analysis. A Wilcoxon rank sum test was applied to the Delta TSC (=TSCmuscle - TSCskin) series of males and females to examine if they were significantly different. Finally, a multiple linear regression was utilized to account for the effects from two potential confounders, age and body mass index (BMI). We found that sodium content appears to be higher in skin than in muscle for men, however women tend to have higher muscle sodium than skin sodium. This sex-relevant sodium deposition is statistically significant (P = 3.10 x 10(-5)) by the Wilcoxon rank sum test, and this difference in distribution seems to be more reliable with increasing age. In the multiple linear regression, gender still has a statistically significant effect (P < 1.0 x 10(-4)) on the difference between sodium deposition in muscle and skin, while taking the effects of age and BMI into account. (C) 2016 Elsevier Inc. All rights reserved.

Sodium can accumulate in the interstitium and promote inflammation through poorly defined mechanisms. Here we describe a novel pathway by which dendritic cells (DCs) are activated by increased extracellular sodium (190 mM). We show that sodium entry through the epithelial sodium channel (ENaC) and the sodium hydrogen exchanger (NHE) 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.

Increasing evidence indicated that excess salt consumption can impose risks on human health and a reduction in daily salt intake from the current average of approximately 12 g/d to 5-6 g/d was suggested by public health authorities. The studies on mice have revealed that sodium chloride plays a role in the modulation of the immune system and a high-salt diet can promote tissue inflammation and autoimmune disease. However, translational evidence of dietary salt on human immunity is scarce. We used an experimental approach of fixing salt intake of healthy human subjects at 12, 9, and 6 g/d for months and examined the relationship between salt-intake levels and changes in the immune system. Blood samples were taken from the end point of each salt intake period. Immune phenotype changes were monitored through peripheral leukocyte phenotype analysis. We assessed immune function changes through the characterization of cytokine profiles in response to mitogen stimulation. The results showed that subjects on the high-salt diet of 12 g/d displayed a significantly higher number of immune cell monocytes compared with the same subjects on a lower-salt diet, and correlation test revealed a strong positive association between salt-intake levels and monocyte numbers. The decrease in salt intake was accompanied by reduced production of proinflammatory cytokines interleukin (IL)-6 and IL-23, along with enhanced producing ability of anti-inflammatory cytokine IL-10. These results suggest that in healthy humans high-salt diet has a potential to bring about excessive immune response, which can be damaging to immune homeostasis, and a reduction in habitual dietary salt intake may induce potentially beneficial immune alterations.

Immune cells regulate a hypertonic microenvironment in the skin; however, the biological advantage of increased skin Na(+) concentrations is unknown. We found that Na(+) accumulated at the site of bacterial skin infections in humans and in mice. We used the protozoan parasite Leishmania major as a model of skin-prone macrophage infection to test the hypothesis that skin-Na(+) storage facilitates antimicrobial host defense. Activation of macrophages in the presence of high NaCl concentrations modified epigenetic markers and enhanced p38 mitogen-activated protein kinase (p38/MAPK)-dependent nuclear factor of activated T cells 5 (NFAT5) activation. This high-salt response resulted in elevated type-2 nitric oxide synthase (Nos2)-dependent NO production and improved Leishmania major control. Finally, we found that increasing Na(+) content in the skin by a high-salt diet boosted activation of macrophages in a Nfat5-dependent manner and promoted cutaneous antimicrobial defense. We suggest that the hypertonic microenvironment could serve as a barrier to infection.

A new discontinuous agarose-gel electrophoresis in 0.05 M HCl/0.04 M barium acetate combined with the highly sensitive visualization technique using toluidine blue/Stains-All has been developed for the simultaneous assaying of hyaluronic acid (HA) and dermatan sulfate (DS) with a detection limit at submicrogram level greater than other conventional procedures. Furthermore, this procedure also separates and reveals chondroitin sulfate (CS). The densitometric analysis of bands resulted in a linear response between 0.01 and 0.5 microg of glycosaminoglycans (GAGs) with correlation coefficients greater than approximately 0.94. Hyaluronic acid and dermatan sulfate extracted and purified from the abdominal skin of six rats were separated and quantified in comparison with the evaluation made by treatment of chondroitin ABC lyase and separation of Delta-disaccharides from hyaluronic acid (DeltadiHA) and dermatan sulfate/chondroitin sulfate (Deltadi4s and Deltadi6s) by HPLC. The total amount of rat skin polysaccharides (hyaluronic acid and dermatan sulfate) was 1.24+/-0.26 microg/mg of tissue by discontinuous agarose-gel electrophoresis and 1.20+/-0.33 microg/mg by HPLC with hyaluronic acid and dermatan sulfate percentages of 50.32+/-2.38 and 49.66+/-2.53, respectively. The analyses also confirmed that hyaluronic acid and dermatan sulfate are the main rat abdominal skin polysaccharides with chondroitin sulfate present in trace amounts. This new agarose-gel electrophoresis could be particularly useful in the study of the distribution of glycosaminoglycans in the skin from different body sites of animals and normal human subjects and may be of importance in understanding the changes that occur in the skin, especially the metabolism of extracellular matrix constituents, in connective tissue disorders.

Background: Sodium accumulation has been considered to take place in the extracellular space, leading to water retention and weight gain. This traditional view has been questioned by recent studies that showed sodium accumulation in humans without expansion of the extracellular volume. We investigated sodium balance and its impact on body weight (BW) during a long-term balance study. Methods: Three healthy subjects were confined to a terrestrial MIR simulator for 135 days under conditions simulating a long-term spaceflight. During the entire isolation period, we meticulously measured daily sodium balance and its contribution to BW. Results: During the study period, subjects accumulated between 2,973 and 7,324 mmol of sodium and gained between 5.1 and 9.3 kg in weight. In all subjects, there was a positive correlation between changes in total-body sodium (ΔTBS) content and BW, reflecting sodium-associated volume expansion. However, toward the end of isolation, sodium gain exceeded weight gain, suggesting that sodium accumulated in an osmotically inactive form. Especially at the onset of the experiment, two subjects showed inverse correlations between ΔTBS and BW. Conclusion: The finding of sodium gain without weight gain is in contradiction to the widely accepted theory that changes in TBS levels are accompanied by changes in extracellular volume. We suggest the existence of a sodium reservoir with the ability to store significant amounts of sodium in an osmotically inactive form. This reservoir might be located in bone, dense connective tissue, or cartilage. © 2002 by the National Kidney Foundation, Inc.

A 34-year-old patient with diabetes insipidus after removal of a hypothalamic tumor, developed difficulties with his treatment and presented with hypernatremia. On admission his blood pressure was normal, he was confused, had polyuria and secondary hyperaldosteronism, and his serum [Na+] was 162 mmol/l. We lowered the serum [Na+] with free water and desmopressin so that after 13 days his serum [Na+] was 141 mmol/l and his symptoms were improved. We reviewed the patient's charts and discovered that his body weight was 79.0 kg with hypernatremia, and 78.5 kg after correction of his serum [Na+] and aldosterone.