Friday Hope: Reducing Sodium Intake: Taming Macrophages, Protecting the Endothelium and Inhibiting the Spike Protein

Salt enhances all things Spike. Reducing sodium intake during acute COVID, Long COVID and Spike Protein Disease/Injury may accelerate the path towards healing.

High NaCl increases production and secretion of vWF from vascular endothelial cells. (A–D and F) HUVECs were exposed to media in which NaCl was elevated for 4 d to the total osmolality indicated in the figure panels. (A) HUVECs adapt to the range of elevated NaCl that occurs in hypernatremia, maintaining logarithmic growth (see also Fig. S2A for images of the cells). (B) High NaCl increases secretion of vWF, but when the elevated NaCl is lowered to the control level (270 mosmol/kg) for 2 d vWF secretion returns to its control level (mean ± SEM, *P < 0.05, t test, n = 5, linearly dependent on NaCl concentration, P = 0.0009). (C) At 270 mosmol/kg vWF multimers are compactly stored in Weibel–Palade bodies (arrow), but when NaCl is increased for 4 d the cells release long fibers of uncondensed vWF multimers (arrow). Green, vWF; blue, nuclei stained with DAPI. The lower panel is a higher magnification of the upper panel. (D) High NaCl has little effect on the level of intracellular vWF protein. (Upper) Representative Western blot image. (Lower) Quantification, relative to 270 mosmol/kg, normalized to tubulin (mean ± SEM, *P < 0.05, t test, n = 3). (F) High NaCl increases vWF mRNA in HUVECs. vWF mRNA level returns to the basal when NaCl is lowered for 2 d (mean ± SEM, *P < 0.05, t test, n = 5, linearly dependent on NaCl concentration, P < 0.0001). (E) vWF protein is higher in the kidney medulla, where interstitial NaCl is very high, than in kidney cortex, where the interstitial concentration of NaCl is similar to that in systemic blood. Immunohistochemical staining for vWF (brown). See also Fig. S2C for colocalization with CD31staining (endothelial cell marker).

To date we have primarily discussed therapeutics we can add to our diets to combat the effects of SARS-CoV-2 and its Spike Protein. However, there are also actions we can take wherein we temporarily subtract items from our diet, also resulting in therapeutic benefits. Such may be the case with salt.

As we know, the endothelium is one of the primary battlegrounds for the Spike Protein. Increased sodium helps the Spike Protein accomplish all of its deleterious functions against the endothelium: It increases leukocyte adhesion, increases secretion of TNF-α, and increases thrombosis.

Endothelial dysfunction is one of the central characteristics of hypertension and is associated with overexpression of leukocyte adhesion molecules and local inflammation. In spontaneously hypertensive rats, overexpression of ICAM-1 (intercellular adhesion molecule-1), MCP-1 (monocyte chemotactic protein-1), and macrophage adhesion ligand-1 (a cell-surface protein expressed in most leukocytes) has been demonstrated in association with increased monocyte endothelial adhesiveness. These findings play a role in end-organ damage.4–7 Takahashi et al4 studied changes in leukocyte adhesiveness induced by sodium intake in Dahl salt–sensitive rats. They examined adhesion of leukocytes to retinal vessels using acridine orange fluoroscopy and scanning laser ophthalmoscope and followed the expression of adhesion molecules in the kidney. After only 3 days of a diet with 8% NaCl, before hypertension developed, leukocyte adhesion was increased in association with increments in mRNA synthesis of MCP-1 and ICAM-1 in the kidney.

Wild et al9 reported that sodium-induced increase in leukocyte adhesion was mediated by reactive oxygen species and endothelial nitric oxide synthase. They further showed that the augmented responses induced by high sodium were present in conditions of nonuniform shear stress: endothelial cells grown in a model of arterial bifurcation show an exaggerated proatherogenic secretion of TNF-α (tumor necrosis factor-α) in response to high sodium concentrations.9

An increase in extracellular sodium within the physiological range is also associated with the stimulation of the coagulation system with increased risk of thrombosis. Studies by Dmitrieva and Burg10 have shown that hypernatremia induced by mild dehydration (mean serum sodium ≈150 mmol/L) upregulates tonicity-regulated transcription factor NFAT5 (nuclear factor of activated T cells 5) and its binding to the promoter of vWF (von Willebrandt factor) gene. vWF protein increases in liver, lung, and blood, and the increment in vWF in blood was associated with increase in the D-dimer fibrin degradation product, indicating ongoing activation of coagulation and thrombolysis by hypernatremia.

Salt Intake and Immunity
https://www.ahajournals.org/doi/10.1161/hypertensionaha.118.11128

All of the above are implicated in what I have called SPED (Spike Protein Endothelial Disease).

We have also discussed at length, in previous posts, how the Spike Protein not only activates macrophages but also polarizes them towards the M1 pro-inflammatory phenotype. Interestingly, salt also does the exact same thing.

Salt also modulates the mononuclear phagocyte system, resulting in promotion of inflammation. The best known of the salt–macrophage interactions is the one related to the buffering of the blood pressure effects of salt retention. Macrophage responses to hyperosmolarity represent a critical element in the regulation of blood pressure and salt homeostasis by inducing TonEBP and VEGFC (vascular endothelial growth factor C)/VEGFR3 (VEGF receptor 3)–mediated modification of lymphatic capillary network that clears electrolytes accumulated in the interstitial fluid.25,26 Of interest, activation of skin macrophages by the increment in interstitial sodium content also promotes antimicrobial defense.27 In addition to the effects on salt homeostasis, salt modifies the balance between proinflammatory and anti-inflammatory macrophages. The concept of 2 macrophage phenotypes has gained general acceptance: the classical proinflammatory M1-type macrophage induced by IFN-γ in T helper–type responses and the M2-type macrophage, induced by Th2 cytokines (IL-4 and IL-13), with activity directed to suppress inflammation and tissue repair.28 In experiments with lipopolysaccharide-induced lung injury, high salt has been found to induce a proinflammatory M1 type in macrophages by a novel mechanism that involves activating p38/cFos or Erk1/2 (extracellular signal-regulated kinases 1/2)/cFos pathways.29 In addition to stimulating M1 macrophages, high-salt diet suppresses anti-inflammatory M2 macrophages by a mechanism involving a reduction in glycolysis and mitochondrial metabolic output, coupled with blunted AKT and mTOR (mammalian target of rapamycin) signaling. The suppression of M2 macrophages contributes to the proinflammatory immune imbalance driven by the stimulation of M1 macrophages.30

Salt Intake and Immunity
https://www.ahajournals.org/doi/10.1161/hypertensionaha.118.11128

There is yet another reason to avoid salt if one is suffering from any form of COVID/Spike Protein disease/injury. High levels of sodium actually enhance the ability of the Spike Protein to bind to our cells.

In this article, we present our results from simulations of the CoV-2 RBD - ACE2 system at different ionic strengths. We performed simulations of the CoV-2 RBD - ACE2 complex at varying salt concentrations over the concentration range from 0.03 M to 0.3 M of calcium and sodium chloride over an individual simulation length of 750 ns in 9 independent simulations (6.75 µs total). We find that the CoV-2 RBD - ACE2 complex is stabilized independent of the salt concentration. We observe a strong negative electrostatic potential at the N-terminal part of CoV-2 RBD and we see that CoV-2 RBD binds even stronger at higher salt concentrations. We find that the dynamics of the N-terminal part of CoV-2 RBD stabilize the protein complex leading to strong collective motions and a stable interface between CoV-2 RBD and ACE2. We state that the sequence of CoV-2 RBD might be optimized for a strong binding to ACE2 at varying salt concentrations at the cellular surface, which acts as a key component in the activation of CoV-2 for its viral entry.

The effect of salt on the dynamics of CoV-2 RBD at ACE2
https://www.biorxiv.org/content/10.1101/2020.10.09.333948v1.full

Clearly, in relation to SARS-CoV-2, reducing sodium intake may go a long way towards recovering one’s health after an infection or viral particle disease/injury. It is my hope that clinicians will discuss a low-sodium or sodium-free diet with those patients who are suffering from Long COVID/Spike Protein disease/injury. It may benefit the rest of us to reduce our sodium intake when enduring a COVID infection.

We have enjoyed a beautiful, clear and cool week here in northern Vermont. The beauty is worthy of a Tolkien Shire summer. I am also happy to report that, week over week, we continue to set a record number of subscribers. Thank you! I will always keep my work free and available to all. Of the 14,164 subscribers, 359 are paid subscribers, which is 2.5%. I am extremely thankful for this support. It is an important goal to reach 700 paid subscribers to keep my work financially sustainable. If one in every forty subscribers were to become a paid subscriber today, that goal would be reached. In essence, “donating a coffee” once a month will keep these engines running. Still, I will continue to work and report back to you, which has always been an honor.

Thank you, as always, for your readership, dialogue and support. Please have a blessed and hopeful weekend.