Immune mechanisms of salt-sensitive hypertension and renal end-organ damage.

Immune mechanisms have been recognized to have a role in the pathogenesis of hypertension, vascular disease and kidney damage in humans and animals for many decades. Contemporary advances in experimentation have permitted a deeper understanding of the mechanisms by which inflammation and immunity participate in cardiovascular disease, and multiple observations have demonstrated strong correlations between the discoveries made in animals and those made in patients with hypertension. Of note, striking phenotypic similarities have been observed in the infiltration of immune cells in the kidney and the development of end-organ damage in patients and animal models with sodium-sensitive hypertension. The available data suggest that an initial salt-induced increase in renal perfusion pressure, which is likely independent of immune mechanisms, induces the infiltration of immune cells into the kidney. The mechanisms mediating immune cell infiltration in the kidney are not well understood but likely involve tissue damage, the direct influence of salt to stimulate immune cell activation, sympathetic nerve stimulation or other factors. The infiltrating cells then release cytokines, free radicals and other factors that contribute to renal damage as well as increased retention of sodium and water and vascular resistance, which lead to the further development of hypertension.

Analysis of Sodium Chloride Intake and Treg/Th17 Lymphocytes in Healthy Individuals and Patients with Rheumatoid Arthritis or Systemic Lupus Erythematosus.

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.

Dietary Salt Exacerbates Experimental Colitis.

The Western diet is characterized by high protein, sugar, fat, and low fiber intake, and is widely believed to contribute to the incidence and pathogenesis of inflammatory bowel disease (IBD). However, high sodium chloride salt content, a defining feature of processed foods, has not been considered as a possible environmental factor that might drive IBD. We set out to bridge this gap. We examined murine models of colitis on either a high salt diet (HSD) or a low salt diet. We demonstrate that an HSD exacerbates inflammatory pathology in the IL-10-deficient murine model of colitis relative to mice fed a low salt diet. This was correlated with enhanced expression of numerous proinflammatory cytokines. Surprisingly, sodium accumulated in the colons of mice on an HSD, suggesting a direct effect of salt within the colon. Similar to the IL-10-deficient model, an HSD also enhanced cytokine expression during infection by Salmonella typhimurium This occurred in the first 3 d of infection, suggesting that an HSD potentiates an innate immune response. Indeed, in cultured dendritic cells we found that high salt media potentiates cytokine expression downstream of TLR4 activation via p38 MAPK and SGK1. A third common colitis model, administration of dextran sodium sulfate, was hopelessly confounded by the high sodium content of the dextran sodium sulfate. Our results raise the possibility that high dietary salt is an environmental factor that drives increased inflammation in IBD.

The influence of sodium on pathophysiology of multiple sclerosis.

Multiple sclerosis (MS) is a chronic, inflammatory, autoimmune disease of the central nervous system, and is an important cause of disability in young adults. In genetically susceptible individuals, several environmental factors may play a partial role in the pathogenesis of MS. Some studies suggests that high-salt diet (>5 g/day) may contribute to the MS and other autoimmune disease development through the induction of pathogenic Th17 cells and pro-inflammatory cytokines in both humans and mice. However, the precise mechanisms of pro-inflammatory effect of sodium chloride intake are not yet explained. The purpose of this review was to discuss the present state of knowledge on the potential role of environmental and dietary factors, particularly sodium chloride on the development and course of MS.

Do high-salt microenvironments drive hypertensive inflammation?

Hypertension is a global epidemic affecting over one billion people worldwide. Despite this, the etiology of most cases of human hypertension remains obscure, and treatment remains suboptimal. Excessive dietary salt and inflammation are known contributors to the pathogenesis of this disease. Recently, it has been recognized that salt can accumulate in the skin and skeletal muscle, producing concentrations of sodium greater than the plasma in hypertensive animals and humans. Such elevated levels of sodium have been shown to alter immune cell function. Here, we propose a model in which tissue salt accumulation causes an immune response leading to renal and vascular inflammation and hypertension.

Implications of dietary salt intake for multiple sclerosis pathogenesis.

In recent years it has become increasingly clear that, alongside genetic risk factors, environmental factors strongly influence the incidence and severity of multiple sclerosis (MS). Based on observations from epidemiological studies, the potential contribution of dietary habits has lately been a matter of debate. Recently it was shown that high salt conditions promote pathogenic T-cell responses and aggravate autoimmunity in an animal model of MS, suggesting that high dietary salt intake might promote central nervous system (CNS) autoimmunity. However, so far, not much is known about the influence of dietary salt intake on MS disease pathology. Here, we discuss the association of dietary salt levels and MS with a special focus on the mechanisms of salt-mediated modulation of the different cell types critically involved in the pathophysiology of MS.

Novel ideas about salt, blood pressure, and pregnancy.

The molecular mechanisms leading to preeclampsia are poorly understood. It has been related to certain immune mechanisms, as well as the pathological regulation of the renin-angiotensin system together with perturbed salt and plasma volume regulation. Finally, a non-specific, vascular, inflammatory response is generated, which leads to the clinical syndrome. Here, we present novel findings in salt (NaCl) metabolism implying that salt is not only important in blood pressure control and volume homeostasis, but also in immune regulation. Sodium and chloride can be stored without accumulation of water in the interstitium at hypertonic concentrations through interactions with proteoglycans. Macrophages in the interstitium act as osmosensors for salt, producing increased amounts of vascular endothelial factor C, which increases the density of the lymph-capillary network and the production of nitric oxide in vessels. An increased interstitial salt concentration activates the innate immune system, especially Th17 cells, and may be an important trigger for autoimmune diseases. The novel findings with the idea of sodium storage and local mechanisms of volume and immune regulation are appealing for preeclampsia and may unify the "immune" and "vascular" hypotheses of preeclampsia.