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Patients with rheumatoid arthritis (RA) have increased hypertension. Tissue sodium may contribute to development and progression of hypertension through immune cell activation. This study aimed to determine if skin sodium content is: 1) higher in RA versus control participants, and 2) associated with blood pressure and disease activity. This cross-sectional study included 32 patients with RA and 33 control participants. Lower leg skin sodium content was measured using magnetic resonance imaging. Ambulatory 24-h blood pressure measurements were obtained, and disease activity was assessed by Disease Activity Score-28 for RA with CRP (DAS28-CRP). Skin sodium content was higher in RA versus control participants (14.22 [12.82, 18.04] vs 12.41 [10.67, 14.55] mmol/L), p = 0.005. Every 1 mmol/l increase in skin sodium was associated with a 1.05 mmHg (95% CI 0.29, 1.82 mmHg, p = 0.009) increase in average 24-h systolic blood pressure in patients with RA, but this relationship was not present in control participants. Skin sodium was not associated with DAS28-CRP or its components. Skin sodium is increased in RA versus control participants and is correlated with 24-h and diurnal systolic blood pressure in patients with RA but not in control participants. Skin sodium content may help explain increased hypertension in patients with RA.

Glycosaminoglycans in the skin interstitium and endothelial surface layer have been shown to be involved in local sodium accumulation without commensurate water retention. Dysfunction of heparan sulfate glycosaminoglycans may therefore disrupt sodium and water homeostasis. In this study, we investigated the effects of combined heterozygous loss of heparan sulfate polymerization genes (exostosin glycosyltransferase 1 and 2; Ext1+/-Ext2+/-) on sodium and water homeostasis. Sodium storage capacity was decreased in Ext1+/-Ext2+/- mice as reflected by a 77% reduction in endothelial surface layer thickness and a lower skin sodium-to-glycosaminoglycan ratio. Also, these mice were characterized by a higher heart rate, increased fluid intake, increased plasma osmolality and a decreased skin water and sodium content, suggesting volume depletion. Upon chronic high sodium intake, the initial volume depletion was restored but no blood pressure increase was observed. Acute hypertonic saline infusion resulted in a distinct blood pressure response: we observed a significant 15% decrease in control mice whereas blood pressure did not change in Ext1+/-Ext2+/- mice. This differential blood pressure response may be explained by the reduced capacity for sodium storage and/or the impaired vasodilation response, as measured by wire myography, which was observed in Ext1+/-Ext2+/- mice. Together, these data demonstrate that defective heparan sulfate glycosaminoglycan synthesis leads to abnormal sodium and water homeostasis and an abnormal response to sodium loading, most likely caused by inadequate capacity for local sodium storage.

A recent study reports that adenosine A2A receptor-mediated lymphangiogenesis increases lymphatic clearance of excess Na+ from the skin and reduces blood pressure, whereas impairment of this process leads to salt-sensitive hypertension. These findings raise intriguing physiological questions regarding the relationships among sodium, water and blood pressure.

The aim of this study is to examine the effects of acute administration of luseogliflozin, the sodium–glucose cotransporter 2 (SGLT2) inhibitor, on renal hemodynamics and tubular functions in anesthetized non-diabetic Sprague Dawley (SD) rats and 5/6 nephrectomized (Nx) SD rats. Renal blood flow (RBF), mean arterial pressure (MAP), and heart rate (HR) were continuously measured and urine was collected directly from the left ureter. Intraperitoneal injection of luseogliflozin (0.9 mg kg −1 ) did not change MAP, HR, RBF, or creatinine clearance (CrCl) in SD rats ( n  = 7). Luseogliflozin significantly increased urine volume, which was associated with significantly increased urinary glucose excretion rates ( P  < 0.001). Similarly, luseogliflozin significantly increased urinary sodium excretion (from 0.07 ± 0.01 µmol min −1 at baseline to 0.76 ± 0.08 µmol min −1 at 120 min; P  < 0.001). Furthermore, luseogliflozin resulted in significantly increased urinary pH ( P  < 0.001) and decreased urinary osmolality and urea concentration ( P  < 0.001) in SD rats. Similarly, in Nx SD rats ( n  = 5–6), luseogliflozin significantly increased urine volume and urinary glucose excretion ( P  < 0.001) without altering MAP, HR, RBF, or CrCl. Luseogliflozin did not elicit any significant effects on the other urinary parameters in Nx SD rats. These data indicate that SGLT2 inhibitor elicits direct tubular effects in non-diabetic rats with normal renal functions.

A Western lifestyle with high salt consumption can lead to hypertension and cardiovascular disease. High salt may additionally drive autoimmunity by inducing T helper 17 (T H 17) cells, which can also contribute to hypertension. Induction of T H 17 cells depends on gut microbiota; however, the effect of salt on the gut microbiome is unknown. Here we show that high salt intake affects the gut microbiome in mice, particularly by depleting Lactobacillus murinus . Consequently, treatment of mice with L. murinus prevented salt-induced aggravation of actively induced experimental autoimmune encephalomyelitis and salt-sensitive hypertension by modulating T H 17 cells. In line with these findings, a moderate high-salt challenge in a pilot study in humans reduced intestinal survival of Lactobacillus spp., increased T H 17 cells and increased blood pressure. Our results connect high salt intake to the gut–immune axis and highlight the gut microbiome as a potential therapeutic target to counteract salt-sensitive conditions. High salt intake changed the gut microbiome and increased T H 17 cell numbers in mice, and reduced intestinal survival of Lactobacillus species, increased the number of T H 17 cells and increased blood pressure in humans. Gut microbes worth their salt The role of the gut microbiota in human disease is becoming increasingly recognized. In this study, Dominik Müller and colleagues report that a diet high in salt alters the composition of the gut microbiota in mice, causing pronounced depletion of the commensal Lactobacillus murinus and reduced production of indole metabolites. Previous work has suggested that a high salt diet leads to the generation of pathogenic T helper 17 (T H 17) cells, which have been linked to hypertension and autoimmunity. The authors show that treatment of mice on a high salt diet with L. murinus prevents salt-induced aggravation of actively induced autoimmune encephalomyelitis and salt-sensitive hypertension, through the suppression of T H 17 cells. In a pilot study in a small number of humans, the authors also show that high-salt challenge induces an increase in blood pressure and T H 17 cells, associated with a reduction in Lactobacillus in the gut. However, future work is required to determine whether the findings for mice are translatable to humans.

We have previously reported that sodium is stored in skin and muscle. The amounts stored in hemodialysis (HD) patients are unknown. We determined whether 23Na magnetic resonance imaging (sodium-MRI) allows assessment of tissue sodium and its removal in 24 HD patients and 27 age-matched healthy controls. We also studied 20 HD patients before and shortly after HD with a batch dialysis system with direct measurement of sodium in dialysate and ultrafiltrate. Age was associated with higher tissue sodium content in controls. This increase was paralleled by an age-dependent decrease of circulating levels of vascular endothelial growth factor-C (VEGF-C). Older (>60 years) HD patients showed increased sodium and water in skin and muscle and lower VEGF-C levels compared with age-matched controls. After HD, patients with low VEGF-C levels had significantly higher skin sodium content compared with patients with high VEGF-C levels (low VEGF-C: 2.3ng/ml and skin sodium: 24.3mmol/l; high VEGF-C: 4.1ng/ml and skin sodium: 18.2mmol/l). Thus, sodium-MRI quantitatively detects sodium stored in skin and muscle in humans and allows studying sodium storage reduction in ESRD patients. Age and VEGF-C-related local tissue-specific clearance mechanisms may determine the efficacy of tissue sodium removal with HD. Prospective trials on the relationship between tissue sodium content and hard end points could provide new insights into sodium homeostasis, and clarify whether increased sodium storage is a cardiovascular risk factor.

Objective: To develop and validate an automated segmentation algorithm for the lower leg using a multi-parametric magnetic resonance imaging protocol. Methods: An automated algorithm combining active contour and intensity-based thresholding methods was developed to identify skin and muscle regions from proton Dixon MR images of the lower leg. Tissue sodium concentration was then computed using contemporaneously acquired sodium images with calibrated phantoms in the field of view. Resulting sodium concentration measurements were compared to a gold standard manual segmentation in 126 scans. Results: Most cases had no observable errors in segmentation of muscle and skin. Six cases had minor errors that were not expected to affect quantification; in the worst, 126 mm2 (2%) of a muscle area of 8,042 mm2 was misclassified. In one case the algorithm failed to separate the tibia from the muscle compartment. Correlation between automated and manual measurements of sodium concentration was R2 = 0.84 for skin, R2 = 0.99 for muscle. Additionally, the RMSE was 2.4mM for skin and 0.5mM for muscle; the observed physiological range was 8.5 to 37.4mM. Conclusion: For the purpose of estimating sodium concentrations in muscle and skin compartments, the automated segmentations provided equally accurate results compared to the more time-intensive manual segmentations. Sodium quantification serves as a biomarker for disease progression, which would assist with early diagnostic treatments. The proposed algorithm will improve workflow, reproducibility, and consistency in such studies.

A Western lifestyle with high salt consumption can lead to hypertension and cardiovascular disease. High salt may additionally drive autoimmunity by inducing T helper 17 (T 17) cells, which can also contribute to hypertension. Induction of T 17 cells depends on gut microbiota; however, the effect of salt on the gut microbiome is unknown. Here we show that high salt intake affects the gut microbiome in mice, particularly by depleting Lactobacillus murinus. Consequently, treatment of mice with L. murinus prevented salt-induced aggravation of actively induced experimental autoimmune encephalomyelitis and salt-sensitive hypertension by modulating T 17 cells. In line with these findings, a moderate high-salt challenge in a pilot study in humans reduced intestinal survival of Lactobacillus spp., increased T 17 cells and increased blood pressure. Our results connect high salt intake to the gut-immune axis and highlight the gut microbiome as a potential therapeutic target to counteract salt-sensitive conditions.

Natriuretic regulation of extracellular fluid volume homeostasis includes suppression of the renin-angiotensin-aldosterone system, pressure natriuresis, and reduced renal nerve activity, actions that concomitantly increase urinary Na+ excretion and lead to increased urine volume. The resulting natriuresis-driven diuretic water loss is assumed to control the extracellular volume. Here, we have demonstrated that urine concentration, and therefore regulation of water conservation, is an important control system for urine formation and extracellular volume homeostasis in mice and humans across various levels of salt intake. We observed that the renal concentration mechanism couples natriuresis with correspondent renal water reabsorption, limits natriuretic osmotic diuresis, and results in concurrent extracellular volume conservation and concentration of salt excreted into urine. This water-conserving mechanism of dietary salt excretion relies on urea transporter-driven urea recycling by the kidneys and on urea production by liver and skeletal muscle. The energy-intense nature of hepatic and extrahepatic urea osmolyte production for renal water conservation requires reprioritization of energy and substrate metabolism in liver and skeletal muscle, resulting in hepatic ketogenesis and glucocorticoid-driven muscle catabolism, which are prevented by increasing food intake. This natriuretic-ureotelic, water-conserving principle relies on metabolism-driven extracellular volume control and is regulated by concerted liver, muscle, and renal actions.

IntroductionTypical Western diet, rich in salt, contributes to autoimmune disease development. However, conflicting reports exist about the effect of salt on neutrophil effector functions, also in the context of arthritis.MethodsWe investigated the effect of sodium chloride (NaCl) on neutrophil viability and functions in vitro , and in vivo employing the murine K/BxN-serum transfer arthritis (STA) model.Results and discussionThe effects of NaCl and external reactive oxygen species (H2O2) were further examined on osteoclasts in vitro. Hypertonic sodium-rich media caused primary/secondary cell necrosis, altered the nuclear morphology, inhibited phagocytosis, degranulation, myeloperoxidase (MPO) peroxidation activity and neutrophil extracellular trap (NET) formation, while increasing total ROS production, mitochondrial ROS production, and neutrophil elastase (NE) activity. High salt diet (HSD) aggravated arthritis by increasing inflammation, bone erosion, and osteoclast differentiation, accompanied by increased NE expression and activity. Osteoclast differentiation was decreased with 25 mM NaCl or 100 nM H2O2 addition to isotonic media. In contrast to NaCl, external H2O2 had pro-resorptive effects in vitro . We postulate that in arthritis under HSD, increased bone erosion can be attributed to an enhanced oxidative milieu maintained by infiltrating neutrophils, rather than a direct effect of NaCl.