Tissue sodium excess is not hypertonic and reflects extracellular volume expansion

Our understanding of Na+ homeostasis has recently been reshaped by the notion of skin as a depot for Na+ accumulation in multiple cardiovascular diseases and risk factors. The proposed water-independent nature of tissue Na+ could induce local pathogenic changes, but lacks firm demonstration. Here, we show that tissue Na+ excess upon high Na+ intake is a systemic, rather than skin-specific, phenomenon reflecting architectural changes, i.e. a shift in the extracellular-to-intracellular compartments, due to a reduction of the intracellular or accumulation of water-paralleled Na+ in the extracellular space. We also demonstrate that this accumulation is unlikely to justify the observed development of experimental hypertension if it were water-independent. Finally, we show that this isotonic skin Na+ excess, reflecting subclinical oedema, occurs in hypertensive patients and in association with aging. The implications of our findings, questioning previous assumptions but also reinforcing the importance of tissue Na+ excess, are both mechanistic and clinical. Na+ has been suggested to accumulate in tissues, particularly skin, in a hypertonic manner and to exert local pathogenic effects. Here, we reappraise this phenomenon which is systemic in nature and reflects isotonic changes in the relative extracellular volume in tissues, e.g. subclinical oedema; as such, it occurs in human hypertension and aging.