High-Salt Diet Causes Osmotic Gradients and Hyperosmolality in Skin Without Affecting Interstitial Fluid and Lymph

Abstract

A commonly accepted core mechanism in fluid volume and blood pressure regulation is the parallel relationship between body Na + and extracellular fluid content. 1 It is assumed that Na + readily equilibrates between the intravascular and interstitial compartments that together constitute the extracellular fluid and that Na + concentrations are not remarkably different between the interstitial and intravascular volume. This idea is based on the relatively simple physicochemical concept of passive body fluid equilibrium in closed systems. 2 To maintain blood pressure homeostasis, body fluid volume and thereby body Na + content has to be maintained within narrow limits.In long-term observations in humans, however, several studies have shown that considerable amounts of Na + are retained or removed from the subjects' bodies without commensurate water retention or loss. [3][4][5][6] This finding suggests that Na + could be stored somewhere in the body without commensurate water retention and thereby be inactive from a fluid balance viewpoint. 7 Previously unidentified extrarenal, tissue-specific regulatory mechanisms that control the release and storage of Na + from a kidney-independent reservoir are a requirement in this scenario, thereby questioning the usual notion of a 2-compartment model. 2 Later studies have indicated that skin might serve as major Na + reservoir. [8][9][10] An implication of these observations might be that there is not a strict isotonicity of all body fluids and that skin electrolyte concentrations do not necessarily equilibrate with blood electrolytes.One consequence of such electrolyte accumulation in excess of water would be that it might cause local hypertonicity. Indeed, using vapor pressure osmometry, we recently demonstrated that Na + accumulation in skin as a consequence of feeding the rats a high-salt diet (HSD) results in a tissue that is hyperosmotic relative to plasma.11 Supporting this notion, interstitial fluid (IF) sampled by microdialysis was found to be ≈10 mosmol/kg, and the Na + concentration in tissue regions presumed to be lymphatics ≈20 mmol/L higher than plasma. 11Such electrolyte gradients would, even with a low capillary reflection coefficient, represent formidable transcapillary forces that would favor massive edema formation. Because the fluid accumulation in rats where salt accumulation has been induced by HSD and deoxycorticosterone acetate (DOCA) combined Abstract-The common notion is that the body Na + is maintained within narrow limits for fluid and blood pressure homeostasis. Several studies have, however, shown that considerable amounts of Na + can be retained or removed from the body without commensurate water loss and that the skin can serve as a major salt reservoir. Our own data from rats have suggested that the skin is hypertonic compared with plasma on salt storage and that this also applies to skin interstitial fluid. Even small electrolyte gradients between plasma and interstitial fluid would represent strong edema-generating forces. Because the...

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

“…Our own recent experiments, however, have shown that there are no Na + or osmolal gradients between plasma, interstitium and lymph. 63 Because we found no indications of total ion as well as cation gradients, our observations suggest that there are no anionic gradients, and thereby that the effect of Donnan forces on ISF and lymph ion distribution is negligible, in agreement with predictions discussed above. 62 Clearly, our knowledge on the interaction between ions and the extracellular matrix elements, and how ions are stored in GAGs in normal as well as high-salt situation, is very limited and should be addressed in future studies.…”

“…In a recent series of experiments, we addressed the question of whether the tissue hyperosmolality was reflected in the skin interstitial fluid phase by isolating ISF from implanted wicks or lymph draining skin from the tail. 63 Although we were able to verify that salt accumulation results in an increase in total skin osmolality, skin ISF and lymph osmolality were identical in low-and high-salt diet and deoxycorticosterone (DOCA)-salt rats. Because lymph may be considered as the "gold standard" representative for interstitial fluid in steady-state conditions, 28,29,66 we concluded based on our lymph as well as wick data that interstitial fluid from skin is isosmotic with plasma even if the tissue is hyperosmotic because of salt accumulation.…”

“…Because lymph may be considered as the "gold standard" representative for interstitial fluid in steady-state conditions, 28,29,66 we concluded based on our lymph as well as wick data that interstitial fluid from skin is isosmotic with plasma even if the tissue is hyperosmotic because of salt accumulation. 63 An osmolal gradient between the skin tissue and its constituent ISF might seem counterintuitive and should be sought explained by additional studies.…”

“…118 These findings, however, calls for a more detailed assessment of the gradient in higher resolution to be better able to understand the functional implications of this observation. 63 The role of urea in this context will be of particular interest to explore in the light of the new observations that the body generates urea to conserve water and excrete salt. 99 The observed urea gradient in the skin may contribute in this process, assisted by keratinocytes that control generation of NO in epidermis and upper dermis and thereby contribute to BP regulation.…”

Sodium chloride is an ionic checkpoint for human Th2 cell responses and shapes the atopic skin microenvironment

“…A new model has emerged by which NaCl concentrations are compartmentalized in distinct organs and tissues (46). Especially the skin has been reported to store sodium at concentrations exceeding those of blood and thus to display specialized, yet poorly defined mechanisms to store osmotically inactive NaCl (47).…”