The Uremic Toxins Inorganic Phosphate, Indoxylsulphate, p-Cresylsulphate, and TMAO Induce the Generation of Sulphated Glycosaminoglycans in Aortic Tissue and Vascular Cells via pAKT Signaling: A Missing Link in the “Gut–Matrix Axis”
Gut-derived uremic toxins (UTs) contribute to cardiovascular disorders like atherosclerosis and cardiomyopathy in patients with chronic kidney disease (CKD), causing increased cardiovascular morbidity and mortality. The intermediate steps between higher concentrations of gut-derived UTs and organ da...
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2025-04-01
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| author | Christian Freise Susanne Metzkow Andreas Zappe Monika Ebert Nicola Stolzenburg Julia Hahndorf Jörg Schnorr Kevin Pagel Matthias Taupitz |
| author_facet | Christian Freise Susanne Metzkow Andreas Zappe Monika Ebert Nicola Stolzenburg Julia Hahndorf Jörg Schnorr Kevin Pagel Matthias Taupitz |
| author_sort | Christian Freise |
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| description | Gut-derived uremic toxins (UTs) contribute to cardiovascular disorders like atherosclerosis and cardiomyopathy in patients with chronic kidney disease (CKD), causing increased cardiovascular morbidity and mortality. The intermediate steps between higher concentrations of gut-derived UTs and organ damage caused by UTs are still insufficiently understood. Glycosaminoglycans (GAGs) as components of the extracellular matrix are known to interact with various ligands such as growth factors or receptors, thereby influencing (patho)physiological processes. We previously found that the UT inorganic phosphate (Pi) induces the synthesis and sulphation of the GAGs heparan sulphate and chondroitin sulphate in the rat vascular smooth muscle cell (VSMC) line A7r5 and in the human endothelial cell (EC) line EA.Hy926. The aim of this study was to investigate if other organic UTs modulate GAGs in vascular cells as well. We treated ex vivo cultures of rat aortic rings as well as primary rat VSMCs and human ECs with the UTs Pi, indoxylsulphate (IS), p-cresylsulphate (pCS), trimethylamine N-oxide (TMAO), and urea, and analyzed the samples by histological staining, qPCR, western blot, HPLC, and colorimetric assays. The UT treatment of aortic rings and cells increased contents of sulphated GAGs and hyaluronic acid. UT-treated cells contained higher amounts of 4S- and 6S-sulphated GAGs compared to controls. This was accompanied by altered expressions of genes and proteins relevant for GAG metabolism. Mechanistically, the effects of the UTs on GAGs involve the activation of the PI3K/Akt pathway and of the transcription factor NF-κB. In conclusion, the UT-induced remodeling of the cardiovascular matrix by upregulation of sulphated GAGs and hyaluronic acid in aortic tissue and vascular cells might be a missing link between gut-derived UT and pathophysiological alterations in the cardiovascular system in the sense of a gut–matrix axis. |
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| issn | 2072-6651 |
| language | English |
| publishDate | 2025-04-01 |
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| series | Toxins |
| spelling | doaj-art-5668eeb7e61b4c68bd7b10226a4ed6a22025-08-20T01:56:38ZengMDPI AGToxins2072-66512025-04-0117521710.3390/toxins17050217The Uremic Toxins Inorganic Phosphate, Indoxylsulphate, p-Cresylsulphate, and TMAO Induce the Generation of Sulphated Glycosaminoglycans in Aortic Tissue and Vascular Cells via pAKT Signaling: A Missing Link in the “Gut–Matrix Axis”Christian Freise0Susanne Metzkow1Andreas Zappe2Monika Ebert3Nicola Stolzenburg4Julia Hahndorf5Jörg Schnorr6Kevin Pagel7Matthias Taupitz8Department of Radiology, Campus Mitte, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10117 Berlin, GermanyDepartment of Radiology, Campus Mitte, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10117 Berlin, GermanyDepartment of Biology, Chemistry and Pharmacy, Freie Universität Berlin, 14195 Berlin, GermanyDepartment of Radiology, Campus Mitte, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10117 Berlin, GermanyDepartment of Radiology, Campus Mitte, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10117 Berlin, GermanyDepartment of Radiology, Campus Mitte, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10117 Berlin, GermanyDepartment of Radiology, Campus Mitte, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10117 Berlin, GermanyDepartment of Biology, Chemistry and Pharmacy, Freie Universität Berlin, 14195 Berlin, GermanyDepartment of Radiology, Campus Mitte, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10117 Berlin, GermanyGut-derived uremic toxins (UTs) contribute to cardiovascular disorders like atherosclerosis and cardiomyopathy in patients with chronic kidney disease (CKD), causing increased cardiovascular morbidity and mortality. The intermediate steps between higher concentrations of gut-derived UTs and organ damage caused by UTs are still insufficiently understood. Glycosaminoglycans (GAGs) as components of the extracellular matrix are known to interact with various ligands such as growth factors or receptors, thereby influencing (patho)physiological processes. We previously found that the UT inorganic phosphate (Pi) induces the synthesis and sulphation of the GAGs heparan sulphate and chondroitin sulphate in the rat vascular smooth muscle cell (VSMC) line A7r5 and in the human endothelial cell (EC) line EA.Hy926. The aim of this study was to investigate if other organic UTs modulate GAGs in vascular cells as well. We treated ex vivo cultures of rat aortic rings as well as primary rat VSMCs and human ECs with the UTs Pi, indoxylsulphate (IS), p-cresylsulphate (pCS), trimethylamine N-oxide (TMAO), and urea, and analyzed the samples by histological staining, qPCR, western blot, HPLC, and colorimetric assays. The UT treatment of aortic rings and cells increased contents of sulphated GAGs and hyaluronic acid. UT-treated cells contained higher amounts of 4S- and 6S-sulphated GAGs compared to controls. This was accompanied by altered expressions of genes and proteins relevant for GAG metabolism. Mechanistically, the effects of the UTs on GAGs involve the activation of the PI3K/Akt pathway and of the transcription factor NF-κB. In conclusion, the UT-induced remodeling of the cardiovascular matrix by upregulation of sulphated GAGs and hyaluronic acid in aortic tissue and vascular cells might be a missing link between gut-derived UT and pathophysiological alterations in the cardiovascular system in the sense of a gut–matrix axis.https://www.mdpi.com/2072-6651/17/5/217uremic toxinsinorganic phosphateglycosaminoglycanschronic kidney diseasevascular smooth muscle cellsaortic rings |
| spellingShingle | Christian Freise Susanne Metzkow Andreas Zappe Monika Ebert Nicola Stolzenburg Julia Hahndorf Jörg Schnorr Kevin Pagel Matthias Taupitz The Uremic Toxins Inorganic Phosphate, Indoxylsulphate, p-Cresylsulphate, and TMAO Induce the Generation of Sulphated Glycosaminoglycans in Aortic Tissue and Vascular Cells via pAKT Signaling: A Missing Link in the “Gut–Matrix Axis” Toxins uremic toxins inorganic phosphate glycosaminoglycans chronic kidney disease vascular smooth muscle cells aortic rings |
| title | The Uremic Toxins Inorganic Phosphate, Indoxylsulphate, p-Cresylsulphate, and TMAO Induce the Generation of Sulphated Glycosaminoglycans in Aortic Tissue and Vascular Cells via pAKT Signaling: A Missing Link in the “Gut–Matrix Axis” |
| title_full | The Uremic Toxins Inorganic Phosphate, Indoxylsulphate, p-Cresylsulphate, and TMAO Induce the Generation of Sulphated Glycosaminoglycans in Aortic Tissue and Vascular Cells via pAKT Signaling: A Missing Link in the “Gut–Matrix Axis” |
| title_fullStr | The Uremic Toxins Inorganic Phosphate, Indoxylsulphate, p-Cresylsulphate, and TMAO Induce the Generation of Sulphated Glycosaminoglycans in Aortic Tissue and Vascular Cells via pAKT Signaling: A Missing Link in the “Gut–Matrix Axis” |
| title_full_unstemmed | The Uremic Toxins Inorganic Phosphate, Indoxylsulphate, p-Cresylsulphate, and TMAO Induce the Generation of Sulphated Glycosaminoglycans in Aortic Tissue and Vascular Cells via pAKT Signaling: A Missing Link in the “Gut–Matrix Axis” |
| title_short | The Uremic Toxins Inorganic Phosphate, Indoxylsulphate, p-Cresylsulphate, and TMAO Induce the Generation of Sulphated Glycosaminoglycans in Aortic Tissue and Vascular Cells via pAKT Signaling: A Missing Link in the “Gut–Matrix Axis” |
| title_sort | uremic toxins inorganic phosphate indoxylsulphate p cresylsulphate and tmao induce the generation of sulphated glycosaminoglycans in aortic tissue and vascular cells via pakt signaling a missing link in the gut matrix axis |
| topic | uremic toxins inorganic phosphate glycosaminoglycans chronic kidney disease vascular smooth muscle cells aortic rings |
| url | https://www.mdpi.com/2072-6651/17/5/217 |
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