The interstitium conducts extrarenal storage of sodium and represents a third compartment essential for extracellular volume and blood pressure homeostasis

Abstract

The role of salt in the pathogenesis of arterial hypertension is not well understood. According to the current understanding, the central mechanism for blood pressure (BP) regulation relies on classical studies linking BP and Na balance, placing the kidney at the very centre of long-term BP regulation. To maintain BP homeostasis, the effective circulating fluid volume and thereby body Na content has to be maintained within very narrow limits. From recent work in humans and rats, the notion has emerged that Na could be stored somewhere in the body without commensurate water retention to buffer free extracellular Na and that previously unidentified extrarenal, tissue-specific regulatory mechanisms are operative regulating the release and storage of Na from a kidney-independent reservoir. Moreover, immune cells from the mononuclear phagocyte system not only function as local on-site sensors of interstitial electrolyte concentration, but also, together with lymphatics, act as systemic regulators of body fluid volume and BP. These studies have established new and unexpected targets in studies of BP control and thus the pathophysiology of hypertension: the interstitium/extracellular matrix of the skin, its inherent interstitial fluid and the lymphatic vasculature forming a vessel network in the interstitium. Aspects of the interstitium in relation to Na balance and hypertension are the focus of this review. Taken together, observations of salt storage in the skin to buffer free extracellular Na and macrophage modulation of the extracellular matrix and lymphatics suggest that electrolyte homeostasis in the body cannot be achieved by renal excretion alone, but also relies on extrarenal regulatory mechanisms.

Quantitative Systems Pharmacology: An Exemplar Model‐Building Workflow With Applications in Cardiovascular, Metabolic, and Oncology Drug Development

“…This suggested a missing mechanism for removal of sodium from the circulation. Recent studies have brought to light the role of nonosmotic peripheral sodium storage in regulating sodium balance . Thus, we updated the model with a peripheral nonosmotic sodium storage compartment.…”

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

“…Although this model is grossly oversimplified [6,7], it is still useful for clinical purposes. These body compartments can be estimated using tracer dilution methods, although this is impractical in a clinical setting.…”

“…Building upon older observations, Titze et al [7] designed a new paradigm in which the skin attained a novel role in blood pressure regulation by nonosmotic sodium storage. Recently, Olde Engberink et al [14] observed that after infusion of hypertonic saline in healthy volunteers, only 47% could be retrieved in the urine, suggesting substantial sodium buffering.…”

“…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].…”