Salt Toxicity Promotes Inflammation

The average salt intake of Americans and all modern societies far exceeds what is needed and this excessive intake appears to be promoting many serious diseases including elevated blood pressure (BP) and hypertension (HTN). There is also no doubt that HTN is a major risk factor for damage to the heart and vascular system contributing to damage, heart failure, heart attacks, cardiac arrythmias, stroke, and renal failure. Elevated BP is also associated with loss of cognitive function and dementia. While medications (meds) that lower BP do reduce the risk of CVD events and kidney failure, BP-meds do not eliminate all the risk of a high-salt diet. Indeed, people on BP-meds still have at least twice the risk of CVD events. Recently, we discussed a study that provided a mechanism by which a high-salt (HS) diet promoted stomach cancer. This suggests that excess added salt is damaging the vascular system and other organs in ways not related simply to BP elevation alone. There is growing evidence that a HS diet promotes inflammation in animals. For example, a study in mice found HS intake caused cells in the small intestine to release cytokine interleukin-17 (IL-17), which promotes inflammation as part of the body's immune response. Another study showed HS consumption led to reduced cognitive function in mice and concluded that lowering dietary salt intake and maintaining healthy blood vessels in the brain may stave off dementia by increasing nitric oxide (NO). It had been thought that it was mainly reduced blood flow through constricted and narrowed blood vessels that led to Alzheimer’s. It now appears that it is more the accumulation of phosphorylated tau. This now appears to be due in part to the reduction of NO. Reduced NO was shown to alter the tau protein that contributes to the build-up of tau deposits inside brain cells. Tau deposits have been implicated in the development of Alzheimer's disease in humans (1).Study Links HS Diet to Changes in MonocytesA prospective randomized crossover designed study in nonsmoking healthy male subjects found that a HS diet increased the CCR2 expression on monocytes both in vitro and in vivo. Dr. Vogt and colleagues found that feeding human subjects a HS diet (7,600mg Na/day) for two weeks altered a variety of white blood cells (WBC). He observed an increase in neutrophils and basophils as well as an increase in CCR2 receptors on monocytes. By contrast, when the healthy male subjects (18 to 40y mean 28y) were fed a low-salt (LS) diet (1200mg Na/day) for two weeks reduced CCR2 expression of their monocytes. This study conclusion was it “…demonstrates that HS promotes an inflammatory monocyte phenotype characterized by strongly enhanced expression of CCR2, together with the increased plasma MCP-I, increased trans-endothelial migration of monocytes, and increased human tissue macrophage content. Macrophages demonstrate signs of increased pro-inflammatory priming after [HS] exposure” (2). Research in rodents has shown that by blocking CCR2 receptors they could eliminate the BP raising effect of a HS diet (3). In Dr. Wenstedt’s study, she observed that Systolic BP was 5mmHg higher in her subjects on the HS diet than on the LS diet after two weeks even though none of her subjects had HTN. This suggests that part of the mechanism by which excessive salt intake promotes elevated BP may also involve this inflammatory process.Monocytes are WBC that leave the blood and squeeze between endothelial cells lining the artery wall. They transform into macrophages that are ameba-type cells designed to engulf bacteria, viruses, and dead cells. They also play a prominent role in promoting atherosclerosis by engulfing oxidatively modified cholesterol-rich LDL particle trapped just under the skin-like endothelial cells that line blood vessel walls. However, macrophages cannot break down cholesterol. So the cholesterol accumulates inside these macrophages transforming them into what are called “foam cells”.  Because the accumulated rancid lipids in these macrophages looks like foam under the microscope they have been called “foam cells”. As these foam cells and cholesterol accumulate below the thin layer of endothelial cells and smooth muscle cell layer, they create the fatty yellow streaks. These yellow streaks are visible to the naked eye in large arteries of even many teenage Americans. These yellow streaks are the hallmark of early atherosclerosis. Figure 1 summarizes the role of monocytes and their CCR2 receptors, MCP-1, VCAM-1 lead first to the adherence of monocytes to the endothelial cells. Then stimulates the monocytes to transmigrate between the endothelial cells that line the artery wall. This is likely how the initiation of foam cells and fatty yellow streaks leads to the formation of atherosclerotic plaque formation their release of MCP-1. The activation of the MCP-1/CCR2 axis is associated with progression of atherosclerosis and increased risk of myocardial infarction (4). This increased inflammation of the artery wall leads to unstable atherosclerotic plaques that are more prone to rupture and trigger a hear attack. Bottom Line: This new research expands our understanding of how a HS diet likely contributes the development of HTN, coronary artery disease, heart attacks, stroke, dementia, congestive heart failure and kidney failure. It now seems increasingly likely salt toxicity contributes to several inflammatory diseases. There is also data linking excess salt to the development of other ills such as kidney stones, osteoporosis, some cancers, more headaches, and asthma it is more than likely most Americans would be wise to reduce their salt intake to no more than 3 to <4g per day or a sodium intake of no more than 1200 to 1500mg per day.By James J. Kenney, PhD, FACNReferences:

1. Faraco G, Hochrainer K, SG Segarra, et. al. Dietary salt promotes cognitive impairment through tau phosphorylation. Nature, 2019; DOI: 10.1038/s41586-019-1688-z
2. Wenstedt EFE, Verberk SGS, Kroon J. et.al. Salt increases monocyte CCR2 expression and inflammatory responses in humans. JCI Insight. 2019;4(21):e130508. https://doi.org/10.1172/jci.insight.130508
3. Chan CT, et.al. Reversal of vascular macrophage accumulation and hypertension by a CCR2 antagonist in deooxycortisone/salt-treated mice. Hypertension. 2012;60(5:1207-12
4. Franca CN et.al. Monocyte subtypes and the CCR chemokine receptor in cardiovascular disease. Clin Sci. 2017;131(12):1215-24