Lymphangiogenesis in response to osmotically inactive Na+ storage in the skin

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Recent experimental evidence has shown that, in contrast to the traditional view, large amounts of Na+ can be accumulated in the body without commensurate water retention. Such water-free Na+ retention is achieved either by osmotically inactive Na+ storage (i.e. in the skin), or by osmotically neutral Na+/K+ exchange (i.e. in the skeletal muscle). While this novel concept suggesting an extrarenal control of volume and blood pressure homeostasis seems of considerable clinical importance, given the disturbances of whole body Na+ in heart and kidney disease, and hypertension, the mechanisms of water-free Na+ retention are unclear. This proposal focuses on the circlulatory reaction of the body in response to osmotically inactive Na+ storage in the skin. We hypothesize that the macrophage is a mobile osmosensor that is attracted by local interstitial hyperosmolality and indirectly modulates the interstitial Na+ content by regulating lymphangiogenesis via VEGF-C (vascular endothelial growth factor C) secretion into the interstitial space. This novel concept suggests an important interface between the immune system and total body electrolyte and fluid balance in a regulatory feed-back control system, suggesting for the first time a direct link between dietary salt excess, osmotically inactive Na+ storage, and a chronic inflammatory response.