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Background— Angiotensin (Ang) II–induced target-organ damage involves innate and acquired immunity. Mice deficient for the helix-loop-helix transcription factor inhibitor of differentiation (Id2 −/− ) lack Langerhans and splenic CD8a+ dendritic cells, have reduced natural killer cells, and have altered CD8 T-cell memory. We tested the hypothesis that an alteration in the number and quality of circulating blood cells caused by Id2 deletion would ameliorate Ang II–induced target-organ damage. Methods and Results— We used gene-deleted and transgenic mice. We conducted kidney and bone marrow transplants. In contrast to Ang II–infused Id2 +/− , Id2 −/− mice infused with Ang II remained normotensive and failed to develop albuminuria or renal damage. Bone marrow transplant of Id2 +/− bone marrow to Id2 −/− mice did not restore the blunted blood pressure response to Ang II. Transplantation of Id2 −/− kidneys to Id2 +/− mice also could not prevent Ang II–induced hypertension and renal damage. We verified the Ang II resistance in Id2 −/− mice in a model of local tissue Ang II production by crossing hypertensive mice transgenic for rat angiotensinogen with Id2 −/− or Id2 +/− mice. Angiotensinogen-transgenic Id2 +/− mice developed hypertension, albuminuria, and renal injury, whereas angiotensinogen-transgenic Id2 −/− mice did not. We also found that vascular smooth muscle cells from Id2 −/− mice showed an antisenescence phenotype. Conclusions— Our bone marrow and kidney transplant experiments suggest that alterations in circulating immune cells or Id2 in the kidney are not responsible for Ang II resistance. The present studies identify a previously undefined role for Id2 in the pathogenesis of Ang II–induced hypertension.

Electrolyte and body fluid homeostasis in higher vertebrates is believed to be fully understood. The paradigm is that Na+ is restricted mainly to the extracellular fluid and K+ to the intracellular space, where both ions act to hold water and thereby control the extracellular and intracellular fluid volume by their osmotic activity. Na+ accumulation thus inevitably leads to water retention. The constancy of the extracellular volume is the task of the kidneys, which control the total body Na+ content. More recent data from balance studies in humans have questioned this traditional view, suggesting that large amounts of Na+ can be accumulated without accompanying water retention by osmotically inactive Na+ retention, or by osmotically neutral Na+/K+ exchange. Besides the control of the body Na+ content by the kidneys, redistribution of body electrolytes hence provides an extrarenal regulatory alternative in the maintenance of body fluid volume and blood pressure control.

A high intake of dietary salt (NaCl) has been implicated in the development of hypertension, chronic inflammation, and autoimmune diseases. We have recently shown that salt has a proinflammatory effect and boosts the activation of Th17 cells and the activation of classical, LPS-induced macrophages (M1). Here, we examined how the activation of alternative (M2) macrophages is affected by salt. In stark contrast to Th17 cells and M1 macrophages, high salt blunted the alternative activation of BM-derived mouse macrophages stimulated with IL-4 and IL-13, M(IL-4+IL-13) macrophages. Salt-induced reduction of M(IL-4+IL-13) activation was not associated with increased polarization toward a proinflammatory M1 phenotype. In vitro, high salt decreased the ability of M(IL-4+IL-13) macrophages to suppress effector T cell proliferation. Moreover, mice fed a high salt diet exhibited reduced M2 activation following chitin injection and delayed wound healing compared with control animals. We further identified a high salt-induced reduction in glycolysis and mitochondrial metabolic output, coupled with blunted AKT and mTOR signaling, which indicates a mechanism by which NaCl inhibits full M2 macrophage activation. Collectively, this study provides evidence that high salt reduces noninflammatory innate immune cell activation and may thus lead to an overall imbalance in immune homeostasis.

Background: We showed previously that a high salt diet (HSD) increases cortisol levels in man. We hypothesized HSD induces catabolic urea generation to facilitate renal water conservation during dietary salt excretion. Methods: 16 male mice were pair-fed either a low-salt diet ( Results: HSD increased renal Na clearance, decreased urea clearance and resulted in urinary Na concentration. HSD reduced body weight and lean body mass, indicating catabolic muscle wasting. This catabolic state was paralleled by urea accumulation and increased arginase activity in liver and in skeletal muscle, while renal urea excretion was reduced. Expression of L-arginine:glycine amidinotransferase (AGAT), which generates the creatine precursor guanidino-acetate and is representative for anabolic liver/muscle metabolism, was selectively reduced in the livers of HSD mice. Conclusion: HSD induces urea production and body urea accumulation to allow for water-economizing urinary Na concentration. The liver regulates Na homeostasis and induces catabolism by favoring urea over creatine production. Catabolic skeletal muscle serves as a glutamine reservoir for urea generation in HSD mice, resulting in sarcopenia. Perspectives: Cachexia is associated with increased cardiovascular mortality and heart failure in humans. Our findings link this condition to catabolic urea osmolyte generation for maintaining Na balance.

Objective: Angiogenesis inhibition with the VEGF-inhibitor sunitinib, an established anti-cancer therapy, induces hypertension and proteinuria. Exposed to osmotic stress, the mononuclear-phagocyte-system (MPS) cells produces VEGF-C and exert homeostatic regulatory activity by promoting lymphatic Na+ drainage; interference with this process resulted in salt-sensitive hypertension. Therefore, we hypothesized that sunitinib, via blockade of the VEGF pathway, leads to Na+ accumulation in the skin and salt-sensitive hypertension. Design and Methods: In male WKY rats, mean arterial pressure (MAP) was monitored telemetrically during oral treatment with sunitinib (7 mg/kg.day, n=7-8) or vehicle (n=7-8) after a normal salt diet (NSD: 0.5-1.0% NaCl and tap water) or a high salt diet (HSD: 8% NaCl and saline water) for 2 weeks. After 8 days of sunitinib or vehicle administration, 24-h urine was collected. After sacrificing, blood was collected for biochemical measurements, skin for Na+ concentration ([Na+]) using dry-ashing, and ears for staining of MPS cells (CD68). Results: MAP during NSD was 101±0.9 mmHg. HSD increased MAP by 27±3 mmHg (P Conclusions: Angiogenesis inhibition-induced hypertension is salt-sensitive. The parallel increases in BP and skin [Na+], in the face of unaltered plasma [Na+] and bodyweight, support the existence of a Na+-buffering compartment in the skin that may contribute to the salt-dependent volume and BP homeostasis during VEGF inhibition.

Rationale and Objectives The aim of the work described here was to determine the feasibility of monitoring Na + concentration and distribution in muscle/skin during aerobic/anaerobic exercise with 23 Na magnetic resonance imaging (MRI). Materials and Methods The Na + concentration and water content of muscle/skin of the left lower leg of six healthy subjects (mean age, 26 years; range, 22–30 years; three men and three women) were assessed before and after aerobic/anaerobic cycle ergometry and during recovery with 3-T 23 Na/ 1 H MRI. 23 Na MRI was performed with a custom-made knee coil. A gradient echo sequence with an acquisition time of 3.25 minutes, echo time of 2.07 ms, repetition time of 100 ms, and spatial resolution of 3 × 3 × 30 mm 3 was applied. Phantoms with increasing sodium concentration served for quantification via linear extrapolation. Blood values were determined by blood gas analysis. Results The concentration of Na + significantly increased during anaerobic exercise in all muscle compartments except the medial gastrocnemius muscle, whereas no significant change was observed in most muscle compartments during aerobic exercise (only the soleus muscle exhibited a significant increase in Na + concentration during aerobic exercise: 1.6 ± 1.5 mmol/kg, 4.5%, P = .046). During anaerobic exercise, the mean Na + concentration of the triceps surae and the whole leg increased by 9.0% (3.1 ± 2.1 mmol/kg, P = .016) and 6.5% (2.2 ± 1.3 mmol/kg, P + concentration in most muscle compartments during anaerobic exercise. Na + concentration significantly decreased during recovery after anaerobic and aerobic exercise in all muscle compartments except the soleus. The Na + concentration of the skin did not significantly change during anaerobic/aerobic exercise. Conclusions Sodium 23 MRI allows reliable and noninvasive visualization and quantification of Na + concentration and distribution in muscle and skin during exercise. 23 Na MRI can be used to gain new insights into Na + homeostasis, presumably leading to better comprehension of pathophysiology.

Sodium is the major cation of extracellular fluid (Oh 2015). Together with chloride, sodium is utilized by the body to maintain normal water distribution, osmotic pressure, and anion–cation balance in the extracellular fluid compartment (Tietz et al. 1994). Electrolyte concentrations in the body are essential for proper cardiovascular function and are under renal and hormonal control (Preuss 2001). Increases in blood sodium levels can be caused by diabetes, renal polyuria, diarrhea, insufficient water intake, excessive sweating, or increased dietary sodium intake. Sodium levels decrease with edema, excessive water intake, vomiting, diarrhea, diuretic therapy, renal tubular damage, hyperaldosteronism, or lower dietary intake.

For a compound to be considered a vitamin, it has to be an essential component of the diet, a dietary essential. The elimination of a vitamin from the diet must result in a more or less clearly defined deficiency disease (Bender 2009). Vitamins are classified as either fat soluble or water soluble. In light of the astronauts’ inadequate dietary intake, the use of vitamin and mineral supplements is often debated (Smith et al. 2001). However, the deficient energy intake of the astronauts is clearly the issue having highest priority. If dietary intake increases, the intake of all nutrients, including the vitamins and minerals, will increase. Fat-soluble vitamins (A, D, E, and K) are soluble in lipids and are usually absorbed in fat globules.

Nutrients are required for the structure and function of every cell and each body system, regardless of the environment. However, changes in environment can have significant effects on nutrient metabolism and requirements. Thus, defining the nutrient requirements for spaceflight and ensuring the provision and intake of those nutrients are primary issues for crew health and mission success.

OBJECTIVE: Na+ can be stored in muscle and skin without commensurate water accumulation. The aim of this study was to assess Na+ and H2O in muscle and skin with MRI in acute heart failure patients before and after diuretic treatment and in a healthy cohort. METHODS: Nine patients (mean age 78 years; range 58-87) and nine age and gender-matched controls were studied. They underwent 23Na/1H-MRI at the calf with a custom-made knee coil. Patients were studied before and after diuretic therapy. 23Na-MRI gray-scale measurements of Na+-phantoms served to quantify Na+-concentrations. A fat-suppressed inversion recovery sequence was used to quantify H2O content. RESULTS: Plasma Na+-levels did not change during therapy. Mean Na+-concentrations in muscle and skin decreased after furosemide therapy (before therapy: 30.7+/-6.4 and 43.5+/-14.5 mmol/L; after therapy: 24.2+/-6.1 and 32.2+/-12.0 mmol/L; p

Our body needs energy to keep up all the major functions of the body such as heartbeat, breathing, metabolism, organ function, and much more. The energy needed for maintaining these functions is called basal metabolism and is the amount of energy needed by the body when it is not performing any physical exercise. The rate at which this energy is used is the basal metabolic rate. The energy expenditure for any physical exercise is added on top of the basal metabolic rate. The sum of these two make up most of the total energy expenditure (TEE). However, for digestion of energy-delivering nutrients (the macronutrients: protein, fat, and carbohydrates), our body also needs energy and produces heat from expending it. The production of heat during digestion is a type of thermogenesis. TEE therefore consists of basal metabolism, any energy expenditure because of physical activity, and thermogenesis.

The vitamin B-complex group and vitamin C are the so-called water-soluble vitamins, which dissolve in water and are not stored by the body (IOM (Institute of Medicine) Standing Committee on the Scientific Evaluation of Dietary Reference Intakes 1998). As they are eliminated in urine, a continuous daily supply in the diet is required. Eight of the water-soluble vitamins are known as the vitamin B-complex group: folate (folic acid), thiamin (vitamin B1), riboflavin (vitamin B2), niacin (vitamin B3), vitamin B6 (pyridoxine), vitamin B12, biotin, and pantothenic acid. B vitamins fall into two categories. They are involved in the reactions of intermediary metabolism related to energy production and redox status, or they are involved in the transfer of single-carbon units (IOM (Institute of Medicine) Standing Committee on the Scientific Evaluation of Dietary Reference Intakes 1998). Moreover, vitamin C is a water-soluble vitamin and it is essential for humans, as we do not have the ability to biosynthesize the compound from glucose due to the lack of gulonolactone oxidase. Vitamin C functions physiologically as a water-soluble antioxidant. It is a matter of concern that water-soluble vitamins are easily destroyed or washed out during food storage and preparation. Despite the presence of fruits and vegetables in the daily diet, nutrient loss is possible during the storage and processing of food. This is also of concern for spaceflight and especially for long-term spaceflight. The space radiation environment is another critical factor that must be controlled for an adequate intake of water-soluble vitamins (Smith and Zwart 2008). Not all water-soluble vitamins are critical or of concern for crewmembers. In the following discussions, only the spaceflight-relevant water-soluble vitamins are pointed out.

We tested the hypothesis that changes in sodium intake modulate adipose-tissue renin–angiotensin and natriuretic peptide system gene expression in humans. We studied 9 healthy young men in a metabolic ward at constant room temperature, humidity, and water, potassium, and calcium intake. Subjects were submitted to 4 different periods of sodium intake, and blood samples, microdialysis samples (interstitial fluid), and biopsies from subcutaneous abdominal adipose tissue were obtained at the end of the low-sodium period (0.7 mmol Na/kg per day) and at the end of the high-sodium period (7.7 mmol Na/kg per day). Urinary sodium excretion was 64±4 mmol per day with the low-sodium diet and 521±8 mmol per day with the high-sodium diet. Systemic and microdialysate sodium concentrations were similar with both interventions. With high-sodium intake, systemic renin activity and aldosterone levels were suppressed, angiotensin-converting enzyme activity did not change, and systemic levels of the atrial natriuretic peptide increased. High-sodium diet increased angiotensin-converting enzyme and atrial natriuretic peptide gene expression in adipose tissue. None of the other genes tested were influenced by changes in dietary sodium intake. Our findings suggest that the adipose-tissue renin–angiotensin system is not part of a feedback mechanism regulating sodium homeostasis and blood pressure. Systemic and adipose-tissue renin–angiotensin systems are regulated at least in part independently from each other. In contrast, systemic atrial natriuretic peptide and adipose-tissue atrial natriuretic peptide respond similarly to changes in sodium intake.

The idea that Na+ retention inevitably leads to water retention is compelling; however, were Na+ accumulation in part osmotically inactive, regulatory alternatives would be available. We speculated that in DOCA-salt rats Na+ accumulation is excessive relative to water. Forty female Sprague-Dawley rats were divided into four subgroups. Groups 1 and 2 (controls) received tap water or 1% saline (salt) for 5 wk. Groups 3 and 4 received subcutaneous DOCA pellets and tap water or salt. Na+, K+, and water were measured in skin, bone, muscle, and total body by desiccation and consecutive dry ashing. DOCA-salt led to total body Na+ excess (0.255 ± 0.022 vs. 0.170 ± 0.010 mmol/g dry wt; P < 0.001), whereas water retention was only moderate (0.685 ± 0.119 vs. 0.648 ± 0.130 ml/g wet wt; P < 0.001). Muscle Na+ retention (0.220 ± 0.029 vs. 0.145 ± 0.021 mmol/g dry wt; P < 0.01) in DOCA-salt was compensated by muscle K+ loss, indicating osmotically neutral Na+/K+ exchange. Skin Na+ retention (0.267 ± 0.049 vs. 0.152 ± 0.014 mmol/g dry wt; P < 0.001) in DOCA-salt rats was not balanced by K+ loss, indicating osmotically inactive skin Na+ storage. We conclude that DOCA-salt leads to tissue Na+ excess relative to water. The relative Na+ excess is achieved by two distinct mechanisms, namely, osmotically inactive Na+ storage and osmotically neutral Na+ retention balanced by K+ loss. This “internal Na+ escape” allows the maintenance of volume homeostasis despite increased total body Na+.

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.

According to the generally accepted view, sodium accumulation in the human body takes place in the extracellular space and is accompanied by an increase in the rate of fluid retention and body weight gain. However, this view was revised in recent studies, which demonstrated that sodium could be accumulated in the human body without expansion of the extracellular space. Sodium exchange and its effect on body weight (BW) were investigated in long-term balance studies. Three apparently healthy volunteer subjects were confined for 135 days to a ground-based model of the main unit of the Mir space station, where they were exposed to model conditions similar to conditions of actual long-term spaceflight. The daily balance of sodium and its contribution to BW changes were studied. During the period of observation, the subjects accumulated 2.973–7.324 mmol of sodium and gained 5.1–9.3 kg. Initially, there was a positive correlation between changes in the total body sodium and the BW, which reflected sodium-dependent extracellular space expansion. However, by the end of the period of isolation, the relative rate of body weight gain was lower than the relative rate of gain in the total body sodium, which suggested that sodium accumulated in an osmotically inactive form. The fact that sodium accumulated without BW gain suggests that isolation of healthy subjects in a hermetically sealed enclosure stimulates sodium accumulation in the body in an osmotically inactive form. The sodium-storing processes activated under these conditions might be localized in bone, connective tissue (skin), or cartilage. Rhythmic variation in the net sodium balance was observed and attributed to oscillations of renal excretion of aldosterone. It is obvious that the depot of osmotically inactive sodium should be taken into account in studies of cardiovascular system function and in pathophysiological approaches to edematous syndrome and hypertension.

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.

Recent evidence suggested that Na can be stored in an osmotically inactive form. We investigated whether osmotically inactive Na storage is reduced in a rat model of salt-sensitive (SS) hypertension. SS and salt-resistant (SR) Dahl-Rapp rats as well as Sprague-Dawley (SD) rats were fed a high (8%)- or low (0.1%)-NaCl diet for 4 wk ( n = 10/group). Mean arterial pressure (MAP) was measured at the end of the experiment. Wet and dry weights, water content, total body Na (TBS), and bone Na content were measured by dessication and dry ashing. MAP was higher in both Dahl strains than in SD rats. In SS rats, 8% NaCl led to Na accumulation, water retention, and hypertension due to impaired renal Na excretion. There was no dietary-induced Na retention in SR and SD rats. TBS was variable; nevertheless, TBS was significantly correlated with body water and MAP in all strains. However, the extent of Na-associated volume and MAP increases was strain specific. Osmotically inactive Na in SD rats was threefold higher than in SS and SR rats. Both SS and SR Dahl rat strains displayed reduced osmotically inactive Na storage capacity compared with SD controls. A predisposition to fluid accumulation and high blood pressure results from this alteration. Additional factors, including impaired renal Na excretion, probably contribute to hypertension in SS rats. Our results draw attention to the role of osmotically inactive Na storage.

Introduction Hyperosmotic stress is well investigated within renal borders, many non-renal tissues are facing fluctuations of osmolality as part of normal, physiological behavior. For example, compared to blood, osmolality of lymphoid tissues, like spleen and thymus, is substantially hypertonic. Therefore, the ability of immune cells to respond and adapt to osmotic stress is crucial for normal immune responses. The osmotic stress response is driven by nuclear factor of activated T cells (NFAT5)/tonicity enhancer binding protein (TonEBP), the only known mammalian osmosensitive transcription factor. It has been shown that mice with a heterozygous deletion of NFAT5 display impaired adaptive immune responses. To specifically analyze the functions of NFAT5 in B lymphocytes, we generated conditional B cell specific knock-out mice. Objectives Using a conditional B cell-specific NFAT5 knock-out mouse model, we want to assess the importance of NFAT5 for B cell development, B cell activation and antibody production. Results NFAT5-deficient mice fed with high salt diet (HSD; 4% NaCl in food and 0.9% NaCl in water) and immunized with TNP-KLH showed impaired IgM and IgG responses compared to wildtype controls. Accordingly, frequencies and numbers of PC and GC B cells were reduced in immunized NFAT5-deficient mice. In support of these findings, we found lower cell numbers and diminished viability of LPS-stimulated NFAT5-deficient B cells cultured in hypertonic medium (+40mM NaCl). Conclusion NFAT5 in B lymphocytes controls antibody responses by controlling B cell activation and survival. Gene expression profiling will now elucidate transcriptional programs and signaling pathways involved in NFAT5-controlled B cell responses.

Skin sodium (Na+) storage, as a physiologically important regulatory mechanism for blood pressure, volume regulation and, indeed, survival, has recently been rediscovered. This has prompted the development of MRI methods to assess Na+ storage in humans (23Na MRI) at 3.0 T. This work examines the feasibility of high in-plane spatial resolution 23Na MRI in skin at 7.0 T. A two-channel transceiver radiofrequency (RF) coil array tailored for skin MRI at 7.0 T (f = 78.5 MHz) is proposed. Specific absorption rate (SAR) simulations and a thorough assessment of RF power deposition were performed to meet the safety requirements. Human skin was examined in an in vivo feasibility study using two-dimensional gradient echo imaging. Normal male adult volunteers (n = 17; mean ± standard deviation, 46 ± 18 years; range, 20–79 years) were investigated. Transverse slices of the calf were imaged with 23Na MRI using a high in-plane resolution of 0.9 × 0.9 mm2. Skin Na+ content was determined using external agarose standards covering a physiological range of Na+ concentrations. To assess the intra-subject reproducibility, each volunteer was examined three to five times with each session including a 5-min walk and repositioning/preparation of the subject. The age dependence of skin Na+ content was investigated. The 23Na RF coil provides improved sensitivity within a range of 1 cm from its surface versus a volume RF coil which facilitates high in-plane spatial resolution imaging of human skin. Intra-subject variability of human skin Na+ content in the volunteer population was

High intake of dietary salt (sodium chloride; NaCl) is attributed to the development of hypertension and cardiovascular disease, and has been proposed to be a cause for the rapid increase in autoimmune diseases in western civilisations. We have recently shown that NaCl has a pro-inflammatory effect and boosts the activation of Th17 cells in vitro, with mice fed a high salt diet having an accelerated and more severe experimental autoimmune encephalomyelitis. In this study, we examine how the activation of alternatively activated (M2) macrophages is affected by NaCl. In stark contrast to our study with Th17 cells, we find that high salt dose-dependently decreased M2 activation in IL-4+IL-13 stimulated BM-derived mouse macrophages. Genes important for M2 activation, including Mrc1, Arg1, Ym1, Fizz1 and PD-L2, all had a blunted expression in the presence of NaCl; an effect which was not observed in tonicity controls (mannitol or urea), implying a specific action of NaCl. Transcription factors important for modulating M2 function (Irf4 and Klf4) were similarly affected. In contrast to our previous findings in Th17 cells, the effect of salt on M2 activation was not mediated via Sgk-1. To explore the mechanism for the effect of NaCl on M2 activation we performed gene expression analysis simultaneously with genome wide epigenetic modification analysis (ChIP-seq for H3K4me3 and H4ac). The results of this revealed that NaCl modulated epigenetic marks at genes important for M2 activation, and additionally identified new genes which were affected. Finally, we asked if these salt-mediated changes in M2 gene profiles, translated into effects on their function. Using an in vitro assay, we found that NaCl-treated M2 macrophages have a reduced ability to suppress the activation of effector T cells. Our study reveals a novel effect of NaCl on M2 activation and function, and gives support to the notion that the modulation of immune cell function by high dietary salt is relevant to hypertension and autoimmune diseases.

Clinical practice and public health advice on salt consumption relies on the generally accepted notion that accurately collected 24-hour urine collections are valid estimates for salt and fluid intake. Reduced salt intake would also reduce thirst and ingestion of sugary drinks accordingly. To test these widely accepted ideas, we performed two independent ultra-long term salt balance studies lasting 105 and 205 days in 10 men simulating a flight to Mars. We fixed dietary intake of all constituents for months at salt intakes of 6, 9, and 12 grams per day and collected all urine. We controlled all environmental factors for rigorous quantitative comparison of urine volume and salt excretion with daily fluid and salt intake. In 1646 collected 24-hour urine samples, our ten subjects recovered 92% of salt they ingested. Due to infradian rhythmical renal salt excretion, only 781 out of 1646 daily urine samples correctly classified a 3 g difference in salt intake (47%). Reducing salt intake from 12 to 6 g reduced 24-hour cortisone excretion (78.3±19.6 vs. 67.2±19.3 μg/d; P

Skin sodium (Na(+) ) storage, as a physiologically important regulatory mechanism for blood pressure, volume regulation and, indeed, survival, has recently been rediscovered. This has prompted the development of MRI methods to assess Na(+) storage in humans ((23) Na MRI) at 3.0 T. This work examines the feasibility of high in-plane spatial resolution (23) Na MRI in skin at 7.0 T. A two-channel transceiver radiofrequency (RF) coil array tailored for skin MRI at 7.0 T (f = 78.5 MHz) is proposed. Specific absorption rate (SAR) simulations and a thorough assessment of RF power deposition were performed to meet the safety requirements. Human skin was examined in an in vivo feasibility study using two-dimensional gradient echo imaging. Normal male adult volunteers (n = 17; mean ± standard deviation, 46 ± 18 years; range, 20-79 years) were investigated. Transverse slices of the calf were imaged with (23) Na MRI using a high in-plane resolution of 0.9 × 0.9 mm(2) . Skin Na(+) content was determined using external agarose standards covering a physiological range of Na(+) concentrations. To assess the intra-subject reproducibility, each volunteer was examined three to five times with each session including a 5-min walk and repositioning/preparation of the subject. The age dependence of skin Na(+) content was investigated. The (23) Na RF coil provides improved sensitivity within a range of 1 cm from its surface versus a volume RF coil which facilitates high in-plane spatial resolution imaging of human skin. Intra-subject variability of human skin Na(+) content in the volunteer population was10.3%. An age-dependent increase in skin Na(+) content was observed (r = 0.78). The assignment of Na(+) stores with (23) Na MRI techniques could be improved at 7.0 T compared with current 3.0 T technology. The benefits of such improvements may have the potential to aid basic research and clinical applications designed to unlock questions regarding the Na(+) balance and Na(+) storage function of skin.

We have recently implicated extrarenal vascular ET-1 in the body’s integrated response to a chronic high salt intake by mediating storage of Na+ within the skin. We hypothesize that upregulation of vascular ET-1 in response to a high salt diet leads to the recruitment of macrophages and lymphocytes to the interstitium of the skin, which promote lymph hyperplasia, all of which provide a buffer for extracellular Na+ homeostasis. In the present study, we determined if vascular endothelial cell ET-1 knockout mice (VEET KO) have reduced vascular cell adhesion molecule expression and increased skin Na+ storage in response to a high salt diet. After 2 weeks of a high NaCl (4%) diet, VEET KO mice have higher total skin Na/water ratio than floxed controls (0.112±0.007 vs. 0.096±0.003 mmol/ml respectively). Floxed control mice have elevated ET-1 mRNA in the aorta compared to animals on low salt (1.38±0.21 vs. 1.05±0.14 fold change respectively, n=6), a response that was completely blunted in VEET KO mice (1.07±0.12...

The lymphocyte adaptor protein LNK (also known as SH2B3) is primarily expressed in hematopoietic and endothelial cells, where it functions as a negative regulator of cytokine signaling and cell proliferation. Single-nucleotide polymorphisms in the gene encoding LNK are associated with autoimmune and cardiovascular disorders; however, it is not known how LNK contributes to hypertension. Here, we determined that loss of LNK exacerbates angiotensin II-induced (Ang II-induced) hypertension and the associated renal and vascular dysfunction. At baseline, kidneys from Lnk-/- mice exhibited greater levels of inflammation, oxidative stress, and glomerular injury compared with WT animals, and these parameters were further exacerbated by Ang II infusion. Aortas from Lnk-/- mice exhibited enhanced inflammation, reduced nitric oxide levels, and impaired endothelial-dependent relaxation. Bone marrow transplantation studies demonstrated that loss of LNK in hematopoietic cells is primarily responsible for the observed renal and vascular inflammation and predisposition to hypertension. Ang II infusion increased IFN-γ-producing CD8+ T cells in the spleen and kidneys of Lnk-/- mice compared with WT mice. Moreover, IFN-γ deficiency resulted in blunted hypertension in response to Ang II infusion. Together, these results suggest that LNK is a potential therapeutic target for hypertension and its associated renal and vascular sequela.

The widely accepted concept of body fluid and electrolyte homeostasis is that Na(+) is restricted mainly to the extracellular fluid and K(+) to the intracellular space, where both ions act to hold water and thereby control the extracellular and intracellular fluid volume by their osmotic activity. Na(+) accumulation thus inevitably leads to water retention. The constancy of the extracellular volume is the task of the kidneys, which control the total body Na(+) content. More recent data have questioned this traditional view, suggesting that large amounts of Na(+) can be accumulated without accompanying water retention by osmotically inactive Na(+) retention, or by osmotically neutral Na(+)/K(+) exchange. Besides the control of the body Na(+) content by the kidneys, redistribution of body electrolytes hence provides an extrarenal regulatory alternative in the maintenance of body fluid volume and blood pressure control.

High dietary salt (NaCl) is a major risk factor for cardiovascular disease (CVD). We have shown that macrophages play a key role in the regulation of interstitial tonicity and that NaCl-induced hypertonicity amplifies T cell (Th17) polarization. We therefore hypothesize that NaCl-induced hypertonicity also affects macrophage polarization. Here we have investigated the effect of NaCl-induced hypertonicity on the IL4/IL13-induced alternative activation of M2 macrophages (AAM). Bone marrow cells from C57BL/6 mice were differentiated in the presence of M-CSF for 7 days to generate M0 macrophages. To induce AAM, M0 macrophages were then incubated with IL4/IL13 for 24h in the presence of 0-40mM NaCl. Quantitative RT-PCR was used to analyze AAM signature genes (e.g. Mrc1, Arg1, Fizz1, Ym-1, PD-L2). NaCl specifically blunted the upregulation of these genes and Klf4 and Irf4 (two transcription factors essential for AAM polarization). In contrast, osmotic stress by mannitol or urea did not have an effect. In previous experiments Sgk1 played a pivotal role in Th17 polarization. In contrast, Sgk1 was not involved in the NaCl-effect on AAM macrophages. It has been shown that histone modifications are essential for AAM. In RAW264.3 macrophages, IL4/IL13 induced an increase in H3K4 trimethylation of a number of genes, including Mrc1. However this H3K4 trimethylation was blunted by NaCl. We also found that incubation with increased concentrations of NaCl altered STAT6 phosphorylation upon IL4/IL13 stimulation. We propose that NaCl-induced hypertonicity alters chromatin modifications and signaling cascades important for the expression of genes essential for AAM polarization and function.

The skin interstitium sequesters excess Na+ and Cl- in salt-sensitive hypertension. Mononuclear phagocyte system (MPS) cells are recruited to the skin, sense the hypertonic electrolyte accumulation in skin, and activate the tonicity-responsive enhancer-binding protein (TONEBP, also known as NFAT5) to initiate expression and secretion of VEGFC, which enhances electrolyte clearance via cutaneous lymph vessels and increases eNOS expression in blood vessels. It is unclear whether this local MPS response to osmotic stress is important to systemic blood pressure control. Herein, we show that deletion of TonEBP in mouse MPS cells prevents the VEGFC response to a high-salt diet (HSD) and increases blood pressure. Additionally, an antibody that blocks the lymph-endothelial VEGFC receptor, VEGFR3, selectively inhibited MPS-driven increases in cutaneous lymphatic capillary density, led to skin Cl- accumulation, and induced salt-sensitive hypertension. Mice overexpressing soluble VEGFR3 in epidermal keratinocytes exhibited hypoplastic cutaneous lymph capillaries and increased Na+, Cl-, and water retention in skin and salt-sensitive hypertension. Further, we found that HSD elevated skin osmolality above plasma levels. These results suggest that the skin contains a hypertonic interstitial fluid compartment in which MPS cells exert homeostatic and blood pressure-regulatory control by local organization of interstitial electrolyte clearance via TONEBP and VEGFC/VEGFR3-mediated modification of cutaneous lymphatic capillary function.

Current teaching states that when sodium intake is increased from low to high levels, total-body sodium (TBNa) and water increase until daily sodium excretion again equals intake. When sodium intake is reduced, sodium excretion briefly exceeds intake until the excess TBNa and water are eliminated, at which point sodium excretion again equals intake. However, careful balance studies oftentimes conflict with this view and long-term studies suggest that TBNa fluctuates independent of intake or body weight. We recently performed the opposite experiment in that we fixed sodium intake for several weeks at three levels of sodium intake and collected all urine made. We found weekly (circaseptan) patterns in sodium excretion that were inversely related to aldosterone and directly to cortisol. TBNa was not dependent on sodium intake but instead exhibited far longer (≥ monthly) infradian rhythms independent of extracellular water, body weight, or blood pressure. The findings are consistent with our ideas on tissue sodium storage and its regulation that we developed on the basis of animal research. We are implementing (23)Na-magnetic resonance imaging (MRI) to pursue open questions on sodium balance in patients. Our findings could be relevant to therapeutic strategies for hypertension and target-organ damage.

The steady-state concept of Na(+) homeostasis, based on short-term investigations of responses to high salt intake, maintains that dietary Na(+) is rapidly eliminated into urine, thereby achieving constant total-body Na(+) and water content. We introduced the reverse experimental approach by fixing salt intake of men participating in space flight simulations at 12 g, 9 g, and 6 g/day for months and tested for the predicted constancy in urinary excretion and total-body Na(+) content. At constant salt intake, daily Na(+) excretion exhibited aldosterone-dependent, weekly (circaseptan) rhythms, resulting in periodic Na(+) storage. Changes in total-body Na(+) (±200-400 mmol) exhibited longer infradian rhythm periods (about monthly and longer period lengths) without parallel changes in body weight and extracellular water and were directly related to urinary aldosterone excretion and inversely to urinary cortisol, suggesting rhythmic hormonal control. Our findings define rhythmic Na(+) excretory and retention patterns independent of blood pressure or body water, which occur independent of salt intake.

In contrast to AL amyloidosis, where clonal plasma cells in bone marrow produce immunoglobulins that are amyloidogenic, and familial amyloidoses in which a mutant protein forms amyloid fibrils, the incidence of AA amyloidoses has been reduced since the treatment of infectious diseases and rheumatoid arthritis improved. AA amyloidoses are due to amyloid formed from serum amyloid A, an acute phase protein produced in response to inflammation. With the reduction of chronic infectious diseases such as tuberculosis or osteomyelitis from the western hemisphere, AA amyloidosis is rarely seen; however, it still occurs in patients with rheumatoid arthritis, inflammatory bowel disease or untreated Mediterranean fever. We report an unusual case of chronic hidradenitis suppurativa leading to AA amyloidosis.

Background: We have shown previously that electrolyte homeostasis is characterized by local regulation of water-free Na + storage in the skin. Macrophages infiltrate the Na + overloaded skin interstitium and induce interstitial electrolyte clearance by TonEBP- / VEGF-C-driven lymph capillary network hyperplasia, therefore providing a buffering mechanism for hypertension. Whether such extrarenal control for volume and blood pressure homeostasis is exclusively achieved by innate immune cells, or whether components of the adaptive immune system modulate this macrophage-specific response, is unclear. We hypothesized that lymphocytes might influence macrophage/TonEBP/VEGF-C driven regulation of skin electrolyte homeostasis and thereby modulate blood pressure. Methods: Seven wt and six RAG -/- -mice, which have no B- or T-cells, were fed a low-salt diet for 2 consecutive weeks. In the end of the experiments, blood pressure was measured via an arterial line, skin electrolyte composition was analyzed, and the macrophage/TonEBP/VEGF-C regulatory axis was characterized. Results: RAG -/- -mice had lower skin Na + (0.11±0.01 vrs. 0.15±0.04 mmol/g; P-/- mice (97±8 vrs. 108±7 mmHg; P Conclusion: We conclude that the absence of B- and T-cells disinhibits VEGF-C expression from subcutaneous macrophages, resulting in inadequate hyperplasia of subcutaneous vessels and extracellular volume loss from skin, which leads to hypotension in RAG -/- -mice. The findings suggest that B- or T-cells are part of a regulatory network in which macrophages modulate interstitial electrolyte homeostasis and blood pressure. Perspectives: Additional experiments in mice with selective B- or T-cell depletion, and adoptive transfer of B- or T-lymphocyte subsets into RAG -/- -mice will allow identification of specific lymphocyte subpopulations involved in inhibition of the TonEBP/VEGF-C regulatory axis in macrophages. Further experiments will also focus on molecular mechanisms of lymphocyte / macrophage interaction. We aim to demonstrate that cells of the innate and adaptive immune system form a network of "homeostatic immune function" for the control of electrolyte and blood pressure homeostasis.

We showed that Na + is stored in the skin without commensurate water retention. In response to interstitial electrolyte load, mononuclear phagocyte system (MPS) cells secrete VEGF C, as regulated by tonicity enhancer binding protein (TonEBP) attaching to the VEGF C promoter. VEGF C induces hyperplasia of skin lymphcapillaries. As IL16 harbors a TonEBP binding site, we tested the hypothesis that IL16 participates in this process. We cultured bone marrow-derived macrophages in isotonic or hypertonic cell culture media and measured IL16 expression. We fed male FVB mice a low salt diet (LSD; < 0.1% NaCl + tap) or a high salt diet (HSD; 4% NaCl + 0.9% saline) for two weeks. We treated the groups with either IL16 specific antibodies or no antibody. After two weeks we measured mean arterial blood pressure (MAP), skin Na + , Cl - , and water content (rSKNa, rSKCl, rSKW), quantified lymphcapillary density, VEGF C and TonEBP expression. IL16 was specifically secreted from macrophages in response to hypertonicity in vitro . HSD increased skin electrolytes, activated TonEBP/VEGF C, and resulted in lymphcapillary hyperplasia. Anti IL16 treatment under LSD increased skin electrolyte, water content and MAP. The IL16 antibody blunted the VEGF C driven lymphcapillary response despite salt load. No differences in skin electrolytes and MAP were found between IL16 antibody treated and untreated mice after HSD. We conclude that IL16 is a regulator of electrolyte and water metabolism and MAP, even in the absence of HSD. The finding that the IL16 promoter contains a TonEBP binding site suggests that IL16 could act as an osmoprotective gene that is involved in regulation of electrolyte homeostasis and MAP control.

Hypertension is the most common cardiovascular risk factor and systolic blood pressure increases continuously with age. Increased vascular stiffness, nitric oxide, renin-angiotensin aldosterone system and salt intake have been implicated. We have developed 23 Na magnetic resonance imaging ( 23 Na MRI) and showed that aldosterone influences tissue Na + storage. We reasoned that Na + might accumulate in tissues with age. We investigated tissue Na + of the lower leg in 113 subjects with 3T 23 Na MRI. Tissue Na + concentration was calibrated by solutions containing 10 to 40 mmol/l of Na + . Prior to 23 Na MRI measurements, a medical history was taken, blood and urine samples were obtained and blood pressure was analyzed in seated position. The age of the 113 subjects analyzed by 23 Na MRI ranged from 22 to 90 years. We studied 44 women and 69 men. Hypertension was diagnosed in 46 subjects (29 men and 17 women). Men showed an exponential increase in tissue Na + with age (muscle R 2 = 0.54, skin R 2 = 0.33). In contrast, tissue Na + in women was only slightly affected by age and increased linearly (skin R 2 = 0.40, muscle R 2 = 0.13). To compare subpopulations, we allocated the participants into three different age groups 65 years. A gender difference in skin tissue Na + could be found throughout all groups with higher levels in men (14.3 vs. 18.1 (65 yrs); p < 0.05). Skin Na + content was elevated in hypertensive women compared to age-matched controls (17.2, n = 12 vs. 21.0 mmol/l, n = 17; p+ values below age-matched subjects (17.6, n = 6 vs. 21.3 mmol/l, n = 24; p < 0.05). We conclude that aging is associated with Na + tissue accumulation with a pronounced gender difference. Skin Na + overload occurs in hypertensive women but not in men. Aldosterone antagonists may reset the age-dependent muscle Na + overload to levels of young healthy controls.

There has been a marked increase in the incidence of autoimmune diseases in the last half-century. While the underlying genetic basis of this class of diseases has recently been elucidated implicating predominantly immune response genes1, changes in environmental factors must ultimate be driving this increase. The recently identified population of interleukin (IL)-17 producing CD4+ helper T cells (Th17 cells) play a pivotal role in autoimmune diseases2. Pathogenic IL-23 dependent Th17 cells have been shown to be critical for the development of experimental autoimmune encephalomyelitis (EAE) an animal model for multiple sclerosis (MS) and genetic risk factors associated with MS are related to the IL23/Th17 pathway1, 2. However, little is known regarding the environmental factors that directly influence Th17 cells. Here we show that increased salt (sodium chloride; NaCl) concentrations found under physiological conditions in vivo dramatically boost the induction of murine and human Th17 cells. High salt conditions activates the p38/MAPK pathway involving the tonicity-responsive enhancer binding protein (TonEBP/NFAT5) and the serum- and glucocorticoid-inducible kinase 1 (SGK1) during cytokine-induced Th17 polarization. Gene silencing or chemical inhibition of p38/MAPK, NFAT5 or SGK1 abrogates the high salt induced Th17 cell development. The Th17 cells generated under high salt display a highly pathogenic and stable phenotype as compared to cells differentiated under normal conditions characterized by the up-regulation of the pro-inflammatory cytokines GM-CSF, TNFα and IL-2. Moreover, mice fed with a high salt diet develop a very severe form of EAE in line with increased central nervous system infiltrating and peripherally induced antigen specific Th17 cells. Thus, increased dietary salt intake might represent an environmental risk factor for the development of autoimmune diseases through the induction of pathogenic Th17 cells.

Hypertension is a common disorder with uncertain etiology. In the last several years, it has become evident that components of both the innate and adaptive immune system play an essential role in hypertension. Macrophages and T cells accumulate in the perivascular fat, the heart and the kidney of hypertensive patients and in animals with experimental hypertension. Various immunosuppressive agents lower blood pressure and prevent end-organ damage. Mice lacking lymphocytes are protected against hypertension, and adoptive transfer of T cells, but not B cells in the animals restores their blood pressure response to stimuli such as angiotensin II or high salt. Recent studies have shown that mice lacking macrophages have blunted hypertension in response to angiotensin II and that genetic deletion of macrophages markedly reduces experimental hypertension. Dendritic cells have also been implicated in this disease. Many hypertensive stimuli have triggering effects on the central nervous system and signals arising from the circumventricular organ seem to promote inflammation. Studies have suggested that central signals activate macrophages and T cells, which home to the kidney and vasculature and release cytokines, including IL-6 and IL-17, which in turn cause renal and vascular dysfunction and lead to blood pressure elevation. These recent discoveries provide a new understanding of hypertension and provide novel therapeutic opportunities for treatment of this serious disease.

Hypertension is linked to disturbed total-body sodium (Na + ) regulation; however, measuring Na + disposition in the body is difficult. We implemented 23 Na magnetic resonance spectroscopy ( 23 Na-MR) and imaging technique ( 23 Na-MRI) at 9.4T for animals and 3T for humans to quantify Na + content in skeletal muscle and skin. We compared 23 Na-MRI data with actual tissue Na + content measured by chemical analysis in animal and human tissue. We then quantified tissue Na + content in normal humans and in patients with primary aldosteronism. We found a 29% increase in muscle Na + content in patients with aldosteronism compared with normal women and men. This tissue Na + was mobilized after successful treatment without accompanying weight loss. We suggest that, after further refinements, this tool could facilitate understanding the relationships between Na + accumulation and hypertension. Furthermore, with additional technical advances, a future clinical use may be possible.

Schmaderer et al1 indicate that they had no success increasing blood pressure further in spontaneously hypertensive rats after giving them clodronate-laden liposomes. They studied spontaneously hypertensive rats and Wistar-Kyoto control rats with radiotelemetry. We cannot explain the findings of this carefully done study; however, we have no data on salt intake and interstitial sodium contents in these animals, no histology was shown, and no information on macrophage disposition was given. We are not macrophage biologists. …

We showed recently that mononuclear phagocyte system (MPS) cells provide a buffering mechanism for salt-sensitive hypertension by driving interstitial lymphangiogenesis, modulating interstitial Na + clearance, and increasing endothelial NO synthase protein expression in response to very high dietary salt via a tonicity-responsive enhancer binding protein/vascular endothelial growth factor C regulatory mechanism. We now tested whether isotonic saline and deoxycorticosterone acetate (DOCA)-salt treatment leads to a similar regulatory response in Sprague-Dawley rats. Male rats were fed a low-salt diet and received tap water (low-salt diet LSD), 1.0% saline (high-salt diet HSD), or DOCA+1.0% saline (DOCA-HSD). To test the regulatory role of interstitial MPS cells, we further depleted MPS cells with clodronate liposomes. HSD and DOCA-HSD led to Na + accumulation in the skin, MPS-driven tonicity-responsive enhancer binding protein/vascular endothelial growth factor C–mediated hyperplasia of interstitial lymph capillaries, and increased endothelial NO synthase protein expression in skin interstitium. Clodronate liposome MPS cell depletion blocked MPS infiltration in the skin interstitium, resulting in unchanged tonicity-responsive enhance binding protein/vascular endothelial growth factor C levels and absent hyperplasia of the lymph capillary network. Moreover, no increased skin endothelial NO synthase protein expression occurred in either clodronate liposome–treated HSD or DOCA-salt rats. Thus, absence of the MPS-cell regulatory response converted a salt-resistant blood-pressure state to a salt-sensitive state in HSD rats. Furthermore, salt-sensitive hypertension in DOCA-salt rats was aggravated. We conclude that MPS cells act as onsite controllers of interstitial volume and blood pressure homeostasis, providing a local regulatory salt-sensitive tonicity-responsive enhancer binding protein/vascular endothelial growth factor C–mediated mechanism in the skin to maintain normal blood pressure in states of interstitial Na + and Cl − accumulation. Failure of this physiological extrarenal regulatory mechanism leads to a salt-sensitive blood pressure response.

Catheter-based renal sympathetic denervation for resistant hypertension: A multicenter safety and proof-of-principle cohort study. Lancet 373: 1275–1281, 2009 {#article-title-2} 1886 1888 Upon the initiative of Smithwick and Thompson (1) of the Massachusetts General Hospital, resection of the splanchnic nerves through a posterior infradiaphragmatic approach plus removal of the sympathetic chain from the level of the eighth dorsal ganglion to the second lumbar ganglion had been used with relative frequency in cases of desperate hypertension at the time when antihypertensive medication was not yet available. In the hands of other investigators, the results were spectacular in a minority of patients but not quite satisfactory in many patients (2,3). Despite improvement of headache, reversal of papilledema in malignant hypertension, etc. , the long-term reduction of BP was quite variable and the 5-yr mortality remained approximately 40% (2). A 10-yr follow-up compared 100 patients who were subjected to thoracolumbar sympathectomy with 1500 patients who received symptomatic therapy. Lasting BP reduction was seen only in one third of the patients (4). Whereas the average BP levels were reduced, occasional BP spikes were not. The average difference of preoperative to postoperative systolic BP values was 21 mmHg. The authors saw reduction of cerebrovascular accidents and less progression of proteinuria and renal dysfunction, but 10-yr mortality was still 41%. Against this background, once effective antihypertensive medication was available, this relatively crude procedure fell out of favor and remained a sleeping beauty. With today's better insight into the role of sympathetic activity in the genesis of hypertension and particularly the role of the kidney in sympathetic activation, there has been a renaissance in the interest of the renal sympathetic nervous system, including its role in primary hypertension—apart from its undoubted role in the hypertension of chronic kidney disease (5–10). Renal disease and, in animal experiments, even minor renal tissue damage such as injection of minute volumes of phenol, trigger afferent signals that ascend via …

For centuries, salt has been regarded as essential to human health. Recent work, however, has provided further evidence that the current dietary intake of salt in Western societies is an important factor in the genesis of essential hypertension and may even partly cause blood pressure-independent target organ damage including renal damage. Accordingly, recent guidelines recommend reduction of daily consumption of salt to 6 g/day. Individuals vary with respect to the increase of blood pressure with increasing salt intake (salt sensitivity); individuals with renal disease are particularly salt sensitive. Salt causes major alterations of renal hemodynamics and accelerates progression. Despite some opinions to the contrary, salt restriction and volume control is particularly important in dialyzed patients. Understanding of how salt affects blood pressure and renal function has recently been advanced in 2 respects. The past concept that salt acts by expanding the extracellular fluid space has been challenged by the demonstration of water-free sodium storage of salt in tissues. Furthermore, salt promotes the secretion of cardiotonic steroids, i.e., mammalian "digitalis." Initial observations suggest a causal role for cardiotonic steroids in the genesis of cardiac abnormalities in advanced renal disease.

Contrasting data are published on the effects of high salt intake (between 300 and 660 mmol/d) on Na balance and fluid retention. In some studies high levels of NaCl intake (400, 440, 550 and 660 mmol/d) led to positive Na balances without fluid retention. To test the relevance of different baseline NaCl intake levels on changes in metabolic water, Na, K, chloride and acid-base balance, a 28 d clinical trial ('Salty Life 6') was carried out in a metabolic ward. Nine healthy male volunteers (aged 25.7 (SD 3.1) years; body mass (BM) 71.4 (SD 4.0) kg) participated in the present study. Four consecutive levels of NaCl intake: low (6 d, 0.7 mmol NaCl/kg BM per d), average normal (6 d, 2.8 mmol NaCl/kg BM per d), high (10 d, 7.7 mmol NaCl/kg BM per d), and low again (6 d, 0.7 mmol NaCl/kg BM per d) were tested. Urine osmolality, extracellular volume (ECV) and plasma volume (PV), cumulative metabolic Na, K, chloride and fluid balances, mRNA expression of two glycosaminoglycan (GAG) polymerisation genes, capillary blood pH, bicarbonate and base excess were measured. During average normal NaCl intake, 193 (SEM 19) mmol Na were retained and ECV (+2.02 (SEM 0.31) litres; P