In salt-sensitive hypertension, the accumulation of Na(+) in tissue has been presumed to be accompanied by a commensurate retention of water to maintain the isotonicity of body fluids. We show here that a high-salt diet (HSD) in rats leads to interstitial hypertonic Na(+) accumulation in skin, resulting in increased density and hyperplasia of the lymphcapillary network. The mechanisms underlying these effects on lymphatics involve activation of tonicity-responsive enhancer binding protein (TonEBP) in mononuclear phagocyte system (MPS) cells infiltrating the interstitium of the skin. TonEBP binds the promoter of the gene encoding vascular endothelial growth factor-C (VEGF-C, encoded by Vegfc) and causes VEGF-C secretion by macrophages. MPS cell depletion or VEGF-C trapping by soluble VEGF receptor-3 blocks VEGF-C signaling, augments interstitial hypertonic volume retention, decreases endothelial nitric oxide synthase expression and elevates blood pressure in response to HSD. Our data show that TonEBP-VEGF-C signaling in MPS cells is a major determinant of extracellular volume and blood pressure homeostasis and identify VEGFC as an osmosensitive, hypertonicity-driven gene intimately involved in salt-induced hypertension.
Western lifestyle with high salt consumption leads to hypertension and cardiovascular disease. High salt may additionally drive autoimmunity by inducing T helper (TH)17 cells, which may also contribute to hypertension. Induction of TH17 cells depends on the gut microbiota, yet the effect of salt on the gut microbiome is unknown. In mouse model systems, we show that high salt intake affects the gut microbiome, particularly by depleting Lactobacillus murinus. Consequently, L. murinus treatment prevents salt-induced aggravation of actively-induced experimental autoimmune encephalomyelitis and salt-sensitive hypertension, by modulating TH17 cells. In line with these findings, moderate high salt challenge in a pilot study in humans reduces intestinal survival of Lactobacillus spp. along with increased TH17 cells and 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.
Dietary salt intake has been investigated in relation to hypertension since the early 20th century.1 Mendelian forms of hypertension have underscored the role of salt intake in the development of hypertension.2 Clinicians have advised patients in terms of their dietary intake and have relied on 24 hour urine collections to verify dietary compliance. 3 Nonetheless, the results have been suboptimal. Clinicians have been limited to measuring Na + in plasma and urine, and the relationship to these sources for determining salt-sensitivity has been disappointing. The issue is important, as salt-sensitivity portends an earlier death. 4 Na + is bound to negatively charged proteoglycans that are very abundant in the skin, the body's largest organ. 5 We showed recently that signaling mechanisms exist in skin that control skin electrolyte storage. 6 When these mechanisms are perturbed, salt-sensitive hypertension results. Translating such findings to humans has been challenging. For that reason, we implemented quantitative 23 Na magnetic resonance imaging ( 23 Na-MRI) to visualize Na + in skin and soft tissues. 7 We reported on rodents measured with 23 Na-MRI and with MR spectroscopy, a small number of normal subjects, and 5 patients with primary aldosteronism, who were studied before and after definitive treatment. We have now extended our observations to larger numbers of normal men and women, as well as to patients with essential hypertension. We believe that 23 Na-MRI shows promise to be of clinical utility in further defining the relationship between salt and hypertension. MethodsWe implemented 23 Na-MRI for quantitative analysis in men; the methods were recently published. 7 We measured Na + content in lower leg muscle and skin with a 23 Na knee-coil (Stark-Contrast, Erlangen, Germany) at 3.0 T with a MRI scanner (Magnetom-Trio, Siemens Healthcare, Erlangen, Germany) using a 2D-FLASH sequence (total acquisition time, TA=13.7 minutes; echo time, TE=2.07 ms; repetition time, TR=100 ms; flip angle, FA=90°; 128 averages, resolution:Abstract-High dietary salt intake is associated with hypertension; the prevalence of salt-sensitive hypertension increases with age. We hypothesized that tissue Na + might accumulate in hypertensive patients and that aging might be accompanied by Na + deposition in tissue. We implemented 23 Na magnetic resonance imaging to measure Na + content of soft tissues in vivo earlier, but had not studied essential hypertension. We report on a cohort of 56 healthy control men and women, and 57 men and women with essential hypertension. The ages ranged from 22 to 90 years.23 Na magnetic resonance imaging measurements were made at the level of the calf. We observed age-dependent increases in Na + content in muscle in men, whereas muscle Na + content did not change with age in women. We estimated water content with conventional MRI and found no age-related increases in muscle water in men, despite remarkable Na + accumulation, indicating water-free Na + storage in muscle. With increasing age, there was ...
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