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Salt Transiently Inhibits Mitochondrial Energetics in Mononuclear Phagocytes.
Geisberger, S, Bartolomaeus, H, Neubert, P, Willebrand, R, Zasada, C, Bartolomaeus, T, McParland, V, Swinnen, D, Geuzens, A, Maifeld, A, et al
Circulation. 2021;(2):144-158
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Abstract
BACKGROUND Dietary high salt (HS) is a leading risk factor for mortality and morbidity. Serum sodium transiently increases postprandially but can also accumulate at sites of inflammation affecting differentiation and function of innate and adaptive immune cells. Here, we focus on how changes in extracellular sodium, mimicking alterations in the circulation and tissues, affect the early metabolic, transcriptional, and functional adaption of human and murine mononuclear phagocytes. METHODS Using Seahorse technology, pulsed stable isotope-resolved metabolomics, and enzyme activity assays, we characterize the central carbon metabolism and mitochondrial function of human and murine mononuclear phagocytes under HS in vitro. HS as well as pharmacological uncoupling of the electron transport chain under normal salt is used to analyze mitochondrial function on immune cell activation and function (as determined by Escherichiacoli killing and CD4+ T cell migration capacity). In 2 independent clinical studies, we analyze the effect of a HS diet during 2 weeks (URL: http://www.clinicaltrials.gov. Unique identifier: NCT02509962) and short-term salt challenge by a single meal (URL: http://www.clinicaltrials.gov. Unique identifier: NCT04175249) on mitochondrial function of human monocytes in vivo. RESULTS Extracellular sodium was taken up into the intracellular compartment, followed by the inhibition of mitochondrial respiration in murine and human macrophages. Mechanistically, HS reduces mitochondrial membrane potential, electron transport chain complex II activity, oxygen consumption, and ATP production independently of the polarization status of macrophages. Subsequently, cell activation is altered with improved bactericidal function in HS-treated M1-like macrophages and diminished CD4+ T cell migration in HS-treated M2-like macrophages. Pharmacological uncoupling of the electron transport chain under normal salt phenocopies HS-induced transcriptional changes and bactericidal function of human and murine mononuclear phagocytes. Clinically, also in vivo, rise in plasma sodium concentration within the physiological range reversibly reduces mitochondrial function in human monocytes. In both a 14-day and single meal HS challenge, healthy volunteers displayed a plasma sodium increase of [Formula: see text] and [Formula: see text] respectively, that correlated with decreased monocytic mitochondrial oxygen consumption. CONCLUSIONS Our data identify the disturbance of mitochondrial respiration as the initial step by which HS mechanistically influences immune cell function. Although these functional changes might help to resolve bacterial infections, a shift toward proinflammation could accelerate inflammatory cardiovascular disease.
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Salt Reduction to Prevent Hypertension and Cardiovascular Disease: JACC State-of-the-Art Review.
He, FJ, Tan, M, Ma, Y, MacGregor, GA
Journal of the American College of Cardiology. 2020;(6):632-647
Abstract
There is strong evidence for a causal relationship between salt intake and blood pressure. Randomized trials demonstrate that salt reduction lowers blood pressure in both individuals who are hypertensive and those who are normotensive, additively to antihypertensive treatments. Methodologically robust studies with accurate salt intake assessment have shown that a lower salt intake is associated with a reduced risk of cardiovascular disease, all-cause mortality, and other conditions, such as kidney disease, stomach cancer, and osteoporosis. Multiple complex and interconnected physiological mechanisms are implicated, including fluid homeostasis, hormonal and inflammatory mechanisms, as well as more novel pathways such as the immune response and the gut microbiome. High salt intake is a top dietary risk factor. Salt reduction programs are cost-effective and should be implemented or accelerated in all countries. This review provides an update on the evidence relating salt to health, with a particular focus on blood pressure and cardiovascular disease, as well as the potential mechanisms.
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Body Fluid-Independent Effects of Dietary Salt Consumption in Chronic Kidney Disease.
Oppelaar, JJ, Vogt, L
Nutrients. 2019;(11)
Abstract
The average dietary salt (i.e., sodium chloride) intake in Western society is about 10 g per day. This greatly exceeds the lifestyle recommendations by the WHO to limit dietary salt intake to 5 g. There is robust evidence that excess salt intake is associated with deleterious effects including hypertension, kidney damage and adverse cardiovascular health. In patients with chronic kidney disease, moderate reduction of dietary salt intake has important renoprotective effects and positively influences the efficacy of common pharmacological treatment regimens. During the past several years, it has become clear that besides influencing body fluid volume high salt also induces tissue remodelling and activates immune cell homeostasis. The exact pathophysiological pathway in which these salt-induced fluid-independent effects contribute to CKD is not fully elucidated, nonetheless it is clear that inflammation and the development of fibrosis play a major role in the pathogenic mechanisms of renal diseases. This review focuses on body fluid-independent effects of salt contributing to CKD pathogenesis and cardiovascular health. Additionally, the question whether better understanding of these pathophysiological pathways, related to high salt consumption, might identify new potential treatment options will be discussed.
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Salt Intake and Immunity.
Afsar, B, Kuwabara, M, Ortiz, A, Yerlikaya, A, Siriopol, D, Covic, A, Rodriguez-Iturbe, B, Johnson, RJ, Kanbay, M
Hypertension (Dallas, Tex. : 1979). 2018;(1):19-23
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Analysis of Sodium Chloride Intake and Treg/Th17 Lymphocytes in Healthy Individuals and Patients with Rheumatoid Arthritis or Systemic Lupus Erythematosus.
Vitales-Noyola, M, Layseca-Espinosa, E, Baranda, L, Abud-Mendoza, C, Niño-Moreno, P, Monsiváis-Urenda, A, Rosenstein, Y, González-Amaro, R
Journal of immunology research. 2018;:9627806
Abstract
We assessed different immune parameters in patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) with low (LSI) and high (HSI) sodium intake. Thirty-eight patients with RA, thirty-seven with SLE, and twenty-eight healthy subjects were studied and classified as LSI or HSI. Levels and suppressive function of CD4+CD25+Foxp3+ and CD4+CD69+Foxp3- Treg cells were determined by flow cytometry in blood samples. Levels and in vitro differentiation of Th17 cells were also assessed. Similar levels of CD4+CD25+Foxp3+ and CD4+CD69+Foxp3- Treg cells were observed in LSI and HSI patients or controls. However, a positive correlation was detected between sodium intake and levels of CD4+CD25+Foxp3+ Treg cells in SLE and a negative association between CD4+CD69+Foxp3- Treg cells and sodium intake in RA. No other significant associations were detected, including disease activity and sodium intake. Moreover, the suppressor activity of CD4+CD25+Foxp3+ and CD4+CD69+Foxp3- Treg cells was similar in LSI and HSI patients or controls. The levels and in vitro differentiation of Th17 cells were also similar in LSI and HSI individuals. Our results suggest that, in the population studied (Mexican mestizo), the level of sodium intake is not apparently associated with different relevant immune parameters in healthy subjects or patients with SLE or RA.
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[Role of renal inflammation in the physiopathology of salt-sensitive hypertension].
Castro Torres, Y, Santos Portela, AE, Garrido Bősze, IM
Archivos de cardiologia de Mexico. 2014;(3):211-7
Abstract
Salt-sensitive hypertension is produced by a decrease in salt renal excretion after a salt overload. Over the last few years, a new theory has been developed to explain this condition based on renal tissue inflammation. This process begins with free radicals production in renal tissue due to oxidative metabolism. Then they favor a renal inflammation mechanism with T-lymphocytes infiltration and other immune cells. Essentially, T-lymphocytes determine an increase in angiotensin ii production which raises sodium and water retention. Association among autoimmune diseases and hypertension may be explained, in part, by the relationship between salt-sensitive hypertension and renal inflammation. The use of antioxidant drugs and the development of new medicaments may be a choice for treating patients affected with this condition.
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Impact of pilot project of Rural Maintenance Programme (RMP) on destitute women: CARE, Bangladesh.
Roy, SK, Bilkes, F, Islam, K, Ara, G, Tanner, P, Wosk, I, Rahman, AS, Chakraborty, B, Jolly, SP, Khatun, W
Food and nutrition bulletin. 2008;(1):67-75
Abstract
BACKGROUND The rate of malnutrition among women in Bangladesh is high, but historically there has not been a specific program focusing on the improvement of the nutritional status of Bangladeshi women. OBJECTIVE To observe changes in the nutritional status of destitute women of the Rural Maintenance Programme (RMP) by incorporating a health and nutrition intervention package with RMP ongoing activities. METHODS An intervention study involving 1,275 poor destitute women was conducted from July 2004 to June 2005 in 17 districts in Bangladesh under two field offices, Mymensingh and Jessore, covering 8 and 9 districts, respectively. The respondents were divided into intervention, comparison, and control groups. All participants in the intervention and comparison groups were paid as part of the RMP and received weekly 30-minute nutrition interventions for 7 weeks in addition to routine training. The comparison group also received RMP training. The control group consisted of women with similar demographic characteristics to the intervention and comparison groups who did not receive pay or any intervention. The intervention was a unique combination of the three components of the UNICEF triangle model (food security, caring practices, and disease control). Data on socioeconomic and anthropometric characteristics, immunization, and vitamin A capsule intake were also collected with the use of a structured questionnaire. RESULTS After the intervention, the mean body weight had significantly increased by 1,333 g in the intervention group and had decreased by 277 g in the control group and 147 g in the comparison group. The body mass index of women in the intervention group had also significantly increased at the end of the study (p < .001). There was a significant increase in the intake of iodized salt in the intervention group as well as increased immunization coverage in all groups. Intake of the first vitamin A capsule by children increased (from 60% to 97%) in the intervention group only. CONCLUSIONS The nutrition pilot intervention was highly effective in improving the nutritional status of women in the RMP.