Abstract
Excess salt (NaCl) intake is closely related to a variety of central nervous system (CNS) diseases characterized by increased cerebral microvascular permeability. However, the link between a high salt diet (HSD) and the breakdown of tight junctions (TJs) remains unclear. In the present study, we found that high salt does not directly influence the barrier between endothelial cells, but it suppresses expression of TJ proteins when endothelial cells are co-cultured with astrocytes. This effect is independent of blood pressure, but depends on the astrocyte activation via the NFκB/MMP-9 signaling pathway, resulting in a marked increase in VEGF expression. VEGF, in turn, induces disruption of TJs by inducing phosphorylation and activation of ERK and eNOS. Correspondingly, the HSD-induced disruption of TJ proteins is attenuated by blocking VEGF using the specific monoclonal antibody Bevacizumab. These results reveal a new axis linking a HSD to increased cerebral microvascular permeability through a VEGF-initiated inflammatory response, which may be a potential target for preventing the deleterious effects of HSD on the CNS.
Highlights
Salt intakes far outweigh the recommended levels in modern diet [1, 2]
We analyzed the expression of tight junctions (TJs)-associated proteins in the brain tissues from rats fed high salt diet (HSD) or normal salt diet (NSD), by using immunofluorescence staining and western blotting (Figure 1C, 1D)
No significant changes were observed in the expression of ZO-1, occluding, and claudin-5 between the HSD and NSD groups, when high salt was fed for 30 days (Figure 1D, 1E)
Summary
Salt (sodium chloride, NaCl) intakes far outweigh the recommended levels in modern diet [1, 2]. A high salt diet (HSD) has long been considered to cause multiple severe vascular complications by up-regulating blood pressure, especially in salt-sensitive patients [3, 4]. Recent studies have suggested a link between HSD, and immune and inflammatory diseases [5,6,7]. The brain is the principle organ impaired by HSD, which has been associated with various cerebral vascular and immuno-inflammatory diseases, such as stroke and multiple sclerosis (MS) [8, 9]. In the central nervous system (CNS), the most important converging point of blood vessels and immunity is the blood-brain barrier (BBB), which acts as a restricted interface insulating the CNS parenchyma from the peripheral circulation [10]. Whether high salt conditions can disrupt the function of the barrier serves as a motivation for our studies
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