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.