Role of the Vascular Wall in Sodium Homeostasis and Salt Sensitivity

Abstract

Excessive sodium intake is associated with both hypertension and an increased risk of cardiovascular events, presumably because of an increase in extracellular volume. The extent to which sodium intake affects extracellular volume and BP varies considerably among individuals, discriminating subjects who are salt-sensitive from those who are salt-resistant. Recent experiments have shown that, other than regulation by the kidney, sodium homeostasis is also regulated by negatively charged glycosaminoglycans in the skin interstitium, where sodium is bound to glycosaminoglycans without commensurate effects on extracellular volume. The endothelial surface layer is a dynamic layer on the luminal side of the endothelium that is in continuous exchange with flowing blood. Because negatively charged glycosaminoglycans are abundantly present in this layer, it may act as an intravascular buffer compartment that allows sodium to be transiently stored. This review focuses on the putative role of the endothelial surface layer as a contributor to salt sensitivity, the consequences of a perturbed endothelial surface layer on sodium homeostasis, and the endothelial surface layer as a possible target for the treatment of hypertension and an expanded extracellular volume. J Am Soc Nephrol 26: 777-783, 2015. doi: 10.1681 In Western society, average daily intake of salt is 8-12 g, thereby greatly exceeding the recommended amount by the World Health Organization of 5 g daily. 1,2 This recommendation is on the basis of the observation that dietary salt intake exceeding 5 g/d, which is equivalent to 2 g or 85 mmol sodium, is associated with hypertension and increased cardiovascular risk in many cohort studies. 3,4 Other than negative effects on cardiovascular morbidity and mortality, high salt intake has also been related to intermediate end points for kidney damage, such as proteinuria, in both patients with CKD and the general population. 5,6 Dietary salt restriction is, therefore, regarded as an important target for improvement of global health. 4 For example, in the United States, it has been estimated that a reduction of dietary salt intake by 3 g/d would reduce annual health costs by $10-$24 billion. 7 Generally, detrimental effects of excessive sodium intake have been linked to expansion of extracellular volume (ECV) and hypertension, which is evidenced by various observations that low sodium reduces BP in both normotensive individuals and individuals with hypertension. 4,8 The increase in BP after dietary sodium excess is highly variable, with some individuals showing a relatively small increase, whereas large BP increases can be observed in others. 9,10 It is likely that these individual variations in salt sensitivity differentially affect cardiovascular and renal risk and may also explain the inconsistent results from population studies investigating the relation between sodium intake and cardiovascular risk. 11 According to Guyton's pressurenatriuresis curve, the kidney regulates long-term BP by altering renal sodium e...

An alternative hypothesis to the widely held view that renal excretion of sodium accounts for resistance to salt-induced hypertension

“…27 Further, Kusche-Vihrog and others have proposed that non-osmotic storage of sodium in the glycocalyx lining of endothelial surfaces may protect against salt-induced increases in blood pressure by impeding sodium ions in plasma from entering endothelial cells. 60, 61 Such impedance of sodium movement may prevent salt-induced increases in endothelial cell sodium concentration that would otherwise cause increases in cell stiffness that interfere with flow-mediated increases in nitric oxide activity and endothelial dependent vasodilation. 60, 61 In addition, Titze and others have indicated that alterations in the storage of non-osmotically active sodium in skin may affect cutaneous vasoreactivity and that this could impact total peripheral resistance and thereby contribute to salt-sensitive hypertension.…”

“…60, 61 Such impedance of sodium movement may prevent salt-induced increases in endothelial cell sodium concentration that would otherwise cause increases in cell stiffness that interfere with flow-mediated increases in nitric oxide activity and endothelial dependent vasodilation. 60, 61 In addition, Titze and others have indicated that alterations in the storage of non-osmotically active sodium in skin may affect cutaneous vasoreactivity and that this could impact total peripheral resistance and thereby contribute to salt-sensitive hypertension. 62, 63 …”

Body Fluids in End-Stage Renal Disease: Statics and Dynamics

“…Using a method in which total BV is compared with an ESL permeable tracer, the ESL, which is estimated to be around 1.5-1.7 l, but was found to be around 0.2 l in patients with type I diabetes mellitus and microalbuminuria [18,19]. Combining the lines of thought regarding the potential sodium buffering roles of the ESL and the skin, it may be hypothesized that a reduction in buffering function of the endothelium allows sodium to enter the endothelial cell.…”

“…Combining the lines of thought regarding the potential sodium buffering roles of the ESL and the skin, it may be hypothesized that a reduction in buffering function of the endothelium allows sodium to enter the endothelial cell. This may increase vascular stiffness [17,18]. Further translocation of sodium into the skin can stimulate lymphangiogenesis through the activation of vascular endothelial growth factor and activate the immune system, most notably through the induction of a pro-inflammatory phenotype of macrophages as well as by stimulation of Th-17 cells [7].…”

“…At first glance, the nonosmotic storage of sodium would seem to be a beneficial adaptation mechanism to buffer extremes in sodium intake. However, this may be offset by adverse effects such as the induction of proinflammatory effects [7,17,18,22] and insulin resistance [23]. In addition, interstitial sodium stores may possibly induce vascular dysfunction [24].…”