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

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.