Distinct osmoregulatory responses to sodium loading in patients with altered glycosaminoglycan structure: a randomized cross-over trial

Abstract

Background By binding to negatively charged polysaccharides called glycosaminoglycans, sodium can be stored in the body—particularly in the skin—without concurrent water retention. Concordantly, individuals with changed glycosaminoglycan structure (e.g. type 1 diabetes (DM1) and hereditary multiple exostosis (HME) patients) may have altered sodium and water homeostasis. Methods We investigated responses to acute (30-min infusion) and chronic (1-week diet) sodium loading in 8 DM1 patients and 7 HME patients in comparison to 12 healthy controls. Blood samples, urine samples, and skin biopsies were taken to investigate glycosaminoglycan sulfation patterns and both systemic and cellular osmoregulatory responses. Results Hypertonic sodium infusion increased plasma sodium in all groups, but more in DM1 patients than in controls. High sodium diet increased expression of nuclear factor of activated t-cells 5 (NFAT5)—a transcription factor responsive to changes in osmolarity—and moderately sulfated heparan sulfate in skin of healthy controls. In HME patients, skin dermatan sulfate, rather than heparan sulfate, increased in response to high sodium diet, while in DM1 patients, no changes were observed. Conclusion DM1 and HME patients show distinct osmoregulatory responses to sodium loading when comparing to controls with indications for reduced sodium storage capacity in DM1 patients, suggesting that intact glycosaminoglycan biosynthesis is important in sodium and water homeostasis. Trial registration These trials were registered with the Netherlands trial register with registration numbers: NTR4095 (https://www.trialregister.nl/trial/3933 at 2013-07-29) and NTR4788 (https://www.trialregister.nl/trial/4645 at 2014-09-12).

Perturbed body fluid distribution and osmoregulation in response to high salt intake in patients with hereditary multiple exostoses

“…This might indicate that an adequate response of extracellular HS increase – allowing increased interstitial tissue sodium accumulation– is necessary to protect ICFV increase. This is in agreement with our previous study, in which we showed that in response to HSD healthy controls showed dermal HS modification, whilst HS modification was absent in HME patients [ 27 ]. Besides the skin also the endothelial surface layer, a thin dynamic HS-rich layer covering endothelial cells, has been identified as an important compartment for sodium accumulation and sodium balance [ [41] , [42] , [43] ].…”

“…On day eight of our intervention a new steady state in sodium and water balance is expected to be achieved [ 45 ]. Furthermore, previous studies showed significant tissue remodeling and local osmoregulatory responses after one week of HSD [ [27] , [46] ]. However, certain limitations need to be considered.…”

“…The disaccharide concentrations were adjusted for creatinine concentrations of the 24-h urine samples. The results of 24-urinary GAG excretion have been described in a previous publication [ [26] , [27] ].…”

Edelman Revisited: Concepts, Achievements, and Challenges

“…All three groups exhibited as a response to high salt intake an increase in the expression of nuclear factor of activated T-cells 5 (NFAT5), which is a transcription factor of cellular response to hypertonic states. Healthy subjects had an increase of skin heparan sulfate, HME patients demonstrated an increase in skin dermatan sulfate rather than heparan sulfate, while patients with type 1 diabetes mellitus had no change in their skin proteoglycans after chronic dietary sodium loading and exhibited a rise in [Na] S significantly higher than the control or HME groups after infusion of the same load of hypertonic saline ( 118 ). One other issue that will need investigation consists of what portion of intracellular potassium that is osmotically inactive ( 119 ) is involved in exchanges with the osmotically active part and participates in the determination of [Na] SW during acute changes of the fraction (TBNa + TBK)/TBW.…”

Salt-Sensitivity of Blood Pressure and Insulin Resistance

“…Previous literature on salt sensitivity regarded body salt balance in terms of the traditional isoosmolar sodium distribution, including the intravascular, interstitial, and intracellular compartments. However, recent studies showed that Na + may accumulate in the interstitium without commensurate water retention but in association with glycosaminoglycans instead ( Titze et al, 2004 ; Wenstedt et al, 2021 ). Whether this Na + is or is not hyperosmolar is controversial ( Rossitto et al, 2020 ), but irrelevant in terms of activation of immune cells, which is due to the Na + concentration, not to its osmolality ( Barbaro et al, 2017 ).…”