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Regulation of Fluid Volume From the Outside: A Role of Glycosaminoglycans in the Skin Interstitium?

H. Wiig

Published 2018 in Circulation: Heart Failure

ABSTRACT

See Article by Nijst et al Few will argue against the central role of salt in fluid volume and blood pressure homeostasis—a role that has passed the test of time through classical studies linking blood pressure and Na+ balance,1 also placing the kidney in the very center of extracellular fluid volume and blood pressure homeostasis.2 This fact notwithstanding, a role for other tissues like the interstitium, mostly in skin, has more recently been suggested in an increasing number of studies.3 Indeed, already Guyton et al4 proposed that strongly negatively charged mucopolysaccharides (now named glycosaminoglycans [GAGs]) could attract and thereby generate a higher density of cations, notably Na+, and that “tissue fluids, pressures, and gel” could influence overall regulation of circulation.5 There are 2 major types of GAGs, hyaluronan having 1 charge and sulfated GAGs having ≤3 charges per disaccharide unit.6 At physiological pH, GAGs have a net negative charge, thus attracting counterions. Although there existed data showing Na+ accumulation in skin, thus challenging the commonly accepted sodium homeostasis principle,7 this challenge was brought to a new level by Titze et al who introduced a new paradigm with regard to salt handling in the body. In studies from humans, rats, and mice, they showed that Na+ can be buffered in the body in kidney-independent reservoirs. This occurs without commensurate water retention, thereby making the Na+ osmotically inactive by association with negatively charged GAGs and thereby invisible to the kidney. In a series of studies, they demonstrated that the skin acts as kidney-independent regulator of the release and storage of Na+, for example,8 making the interstitium and its extracellular matrix and gel phase an additional player in Na+ homeostasis. Without questioning the undisputed role of …

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