Skin Sodium and Hypertension: a Paradigm Shift?

Fig. 1. A novel extra-renal mechanism for buffering dietary salt. Under normal conditions, Na+ binds to negatively charged GAGs in the dermal interstitium, without commensurate water, allowing high concentrations of Na+ to accumulate in the skin. During salt loading, the Na+-binding capacity of GAGs is exceeded and interstitial hypertonicity develops. This leads to an influx of macrophages, which release an osmosensitive transcription factor (TonEBP). This induces the secretion of VEGF-C in an autocrine manner, leading to lymphangiogenesis. The enhanced lymphatic network increases Na+ transport back into the circulation, for eventual removal by the kidneys, preventing a blood pressure rise with salt loading (Adapted from Marvar et al. [42]. Illustrated by Gökçen Ackali)

Fig. 2. Movement of sodium from the intestinal lumen to the skin. [1] Intestinal sodium absorption across the apical membrane of enterocytes is facilitated by (i) Na-H exchange (NHE-2, NHE-3, NHE-8), (ii) cotransport with sugars and phosphates (SGLT-1, GLUT, NaPi2b) and (iii) diffusion through endothelial Na channels (ENaC). Chloride transport occurs via bicarbonate exchange (DRA) and paracellular diffusion. [2] Intracellular sodium is actively pumped across the basal membrane of the intestine by Na-K ATPases. [3] Once in the interstitium, sodium diffuses into the intestinal capillaries for transport through the vasculature. [4] Sodium can diffuse paracellularly into the skin under low salt conditions. Consuming excessive amounts of salt can exaggerate this process by causing damage to the endothelial glycocalyx and reducing barrier effectiveness