Dataset Information

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

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.

SUBMITTER: Agocs R

PROVIDER: S-EPMC7645107 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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

Agócs Róbert R Pap Domonkos D Sugár Dániel D Tóth Gábor G Turiák Lilla L Veréb Zoltán Z Kemény Lajos L Tulassay Tivadar T Vannay Ádám Á Szabó Attila J AJ

Frontiers in physiology 20201023

Sodium (Na<sup>+</sup>) 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 ...[more]

PMID: 33192558

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Project description:Cutaneous lupus erythematosus (CLE) is an autoimmune disease that localizes to the skin and is known to contain elevated glycosaminoglycans (GAGs) on Hale’s stain of skin biopsy specimens. Recently, different GAG species have been shown to have distinct effects on the recruitment and activation of immune cells and stimulation of cytokine production (Taylor and Gallo, FASEB, 2006; 20: 9-22). Thus, we speculate that the elevated GAGs observed in CLE play a role in the local inflammatory process that produces skin lesions in these patients. In order to further investigate a molecular basis for the elevated expression of these GAGs in CLE skin lesions, we would like to determine the gene expression profiles of GAG synthesis, degradation, and modifier genes in lesional and non-lesional skin samples from CLE patients and compare to those from healthy controls. A microarray approach will give us a broader understanding of the genetic regulation of the expression of various GAG species in CLE skin. We will then be able to target future quantitative gene expression experiments by real-time RT-PCR to the genes that are shown to be involved in CLE. In order to accomplish our goal, we would like to examine the GAG gene expression profiles of DLE, TLE, and SCLE subtypes due to the differences in CS and HA staining that we found among these subtypes. Since HA and CS are elevated in DLE and HA in TLE, but not in SCLE, the SCLE samples will also serve as an internal control. We would like to examine both lesional and non-lesional skin biopsies to determine if CLE skin prior to developing a lesion is different at the genetic level from healthy control skin and how it changes once a lesion does develop. We will separate the dermis from the epidermis of the skin biopsies and extract RNA just from the dermis to enrich for dermal fibroblast RNA. We aim to submit four patient biopsies per subtype as well as four samples from healthy control skin for comparison. This number is necessary in order to account for the biologic variability among different patients. We would submit more samples per subtype but are limited by availability of patients in clinic. Thus, we will have a total of 28 samples to submit for microarray. This study design will allow us to analyze the GAG gene expression profiles among different CLE subtypes and enable us to identify which GAc

Dataset Information

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

Publications

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

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