Cyclooxygenase-2 Modulates Glycosaminoglycan Production in the Skin During Salt Overload

Róbert Agócs; Domonkos Pap; Dániel Sugár; Gábor Tóth; Lilla Turiák; Zoltán Veréb; Lajos Kemény; Tivadar Tulassay; Ádám Vannay; Attila J Szabó

doi:10.3389/fphys.2020.561722

Cyclooxygenase-2 Modulates Glycosaminoglycan Production in the Skin During Salt Overload

Front Physiol. 2020 Oct 23:11:561722. doi: 10.3389/fphys.2020.561722. eCollection 2020.

Authors

Róbert Agócs¹, Domonkos Pap², Dániel Sugár¹, Gábor Tóth^{3

4}, Lilla Turiák³, Zoltán Veréb^{5

6

7}, Lajos Kemény^{5

6

7}, Tivadar Tulassay^{1

2}, Ádám Vannay², Attila J Szabó^{1

2}

Affiliations

¹ 1st Department of Pediatrics, Semmelweis University, Budapest, Hungary.
² MTA-SE (Hungarian Academy of Sciences - Semmelweis University) Pediatrics and Nephrology Research Group, Hungarian Academy of Sciences and Semmelweis University, Budapest, Hungary.
³ MS (Mass Spectrometry) Proteomics Research Group, Research Centre for Natural Sciences, Budapest, Hungary.
⁴ Department of Inorganic and Analytical Chemistry, Budapest University of Technology and Economics, Budapest, Hungary.
⁵ Department of Dermatology and Allergology, University of Szeged, Szeged, Hungary.
⁶ MTA-SZTE (Hungarian Academy of Sciences - University of Szeged) Dermatological Research Group, University of Szeged, Szeged, Hungary.
⁷ HCEMM-USZ (Hungarian Centre of Excellence for Molecular Medicine - University of Szeged) Skin Research Group, Szeged, Hungary.

Abstract

Sodium (Na⁺) can accumulate in the skin tissue, sequestered by negatively charged glycosaminoglycans (GAGs). During dietary salt overload, the amount and charge density of dermal GAG molecules - e.g., hyaluronic acid (HA) and chondroitin sulfate (CS) - increases; however, the regulation of the process is unknown. Previously, it has been demonstrated that the level of cyclooxygenase-2 (COX-2) activity and the content of prostaglandin E2 (PGE2) are elevated in the skin due to high-salt consumption. A link between the COX-2/PGE2 system and GAG synthesis was also suggested. We hypothesized that in dermal fibroblasts (DFs) high-sodium concentration activates the COX-2/PGE2 pathway and also that PGE2 increases the production of HA. Our further aim was to demonstrate that the elevation of the GAG content is ceased by COX-2 inhibition in a salt overloaded animal model. For this, we investigated the messenger RNA (mRNA) expression of COX-2 and HA synthase 2 enzymes as well as the PGE2 and HA production of DFs by real-time reverse transcription PCR (qRT-PCR) and ELISA, respectively. The results showed that both high-sodium concentration and PGE2 treatment increases HA content of the media. Sodium excess activates the COX-2/PGE2 pathway in DFs, and COX-2 inhibition decreases the synthesis of HA. In the animal experiment, the HA- and CS disaccharide content in the skin of male Wistar rats was measured using high performance liquid chromatography-mass spectrometry (HPLC-MS). In the skin of rats receiving high-salt diet, the content of both HA- and monosulfated-CS disaccharides increased, whereas COX-2 inhibition blocked this overproduction. In conclusion, high-salt environment could induce GAG production of DFs in a COX-2/PGE2-dependent manner. Moreover, the COX-2 inhibition resulted in a decreased skin GAG content of the salt overloaded rats. These data revealed a new DF-mediated regulation of GAG synthesis in the skin during salt overload.

Keywords: cyclooxygenase-2; dermal fibroblast; glycosaminoglycan; hypertension; hypertonicity; prostaglandin E2; skin; sodium storage.