Abstract: TH-OR30
Distinct Cellular Osmoregulatory Response in the Skin of Patients with Disturbed Glycosaminoglycan Biosynthesis
Session Information
- Molecular Insights in Ion, Acid, and Water Handling
October 22, 2020 | Location: Simulive
Abstract Time: 05:00 PM - 07:00 PM
Category: Fluid, Electrolyte, and Acid-Base Disorders
- 902 Fluid, Electrolyte, and Acid-Base Disorders: Clinical
Authors
- Oppelaar, Jetta J., Amsterdam UMC Locatie AMC, Amsterdam, North Holland, Netherlands
- Wenstedt, Eliane, Amsterdam UMC Locatie AMC, Amsterdam, North Holland, Netherlands
- Rorije, Nienke M.G., Amsterdam UMC Locatie AMC, Amsterdam, North Holland, Netherlands
- Olde Engberink, Rik Hg, Amsterdam UMC Locatie AMC, Amsterdam, North Holland, Netherlands
- Van den born, Bert-jan, Amsterdam UMC Locatie AMC, Amsterdam, North Holland, Netherlands
- Aten, Jan, Amsterdam UMC Locatie AMC, Amsterdam, North Holland, Netherlands
- Vogt, Liffert, Amsterdam UMC Locatie AMC, Amsterdam, North Holland, Netherlands
Background
Several studies have shown that during high Na+ diet (HSD) sodium content of the skin increases. Nuclear factor of activated T cells 5 (NFAT5) is a hypertonicity driven transcription factor responsive to environmental osmotic changes. Sulfated glycosaminoglycans (GAGs) have been suggested to neutralize Na+-induced hypertonic effects by facilitating a dynamic non-osmotic Na+ storage compartment. Patients with diabetes mellitus type 1 (DM1) and hereditary multiple exostoses (HME) display decreased GAG sulfation. We questioned whether these patients show distinct cellular osmoregulatory responses to a HSD.
Methods
We performed an experimental randomized cross-over study in 8 DM1, 7 HME, and 12 healthy males with similar age, BMI and eGFR. All subjects followed both an 8-day low Na+ diet (<50mmol/d) and a HSD (>200mmol/d) in randomized order, separated by a 7-to-10-day washout period. After each diet, blood samples and skin biopsies were obtained. With immunohistochemistry, skin NFAT5 expression and GAG sulfation patterns were semi-quantitatively analyzed by researchers blinded for diet status.
Results
HSD increased dermal NFAT5 expression in controls, whereas in DM1 and HME no changes were observed (Fig1A). In controls, HSD also increased averagely sulfated heparan sulfate in the dermis (Fig1B). During HSD, dermal NFAT5 expression and plasma osmolality were negatively correlated in controls (Fig1C).
Conclusion
In response to HSD, controls showed a hypertonicity-driven response in skin tissue. No hypertonicity-driven changes could be observed in the skin of patients with disturbed GAGs. In controls during HSD, dermal NFAT5 was associated with lower plasma osmolality, suggesting interstitial hypertonicity. Our study implicates that intact GAGs might be important for the skin interstitium to increase hypertonicity and respond to HSD with remodeling the sodium buffering compartment. This underlines the importance of intact GAGs in non-osmotic sodium buffering in humans.