{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T11:26:03Z","timestamp":1773833163526,"version":"3.50.1"},"reference-count":46,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2024,2,22]],"date-time":"2024-02-22T00:00:00Z","timestamp":1708560000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)","award":["372486779 (SFB 1340\/2)"],"award-info":[{"award-number":["372486779 (SFB 1340\/2)"]}]},{"name":"Open Access Publication Fund of Charit\u00e9\u2014Universit\u00e4tsmedizin Berlin","award":["372486779 (SFB 1340\/2)"],"award-info":[{"award-number":["372486779 (SFB 1340\/2)"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Patients with chronic kidney disease (CKD) have a high prevalence of hyperphosphatemia, where uremic toxins like inorganic phosphate (Pi) induce a cardiovascular remodeling. Related disorders like atherosclerosis bear the risk of increased morbidity and mortality. We previously found that Pi stimulates the synthesis and sulfation of the negatively charged glycosaminoglycans (GAGs) heparan sulfate and chondroitin sulfate in vascular smooth muscle cells (VSMC). Similar GAG alterations were detected in VSMC-derived exosome-like extracellular vesicles (EV). These EV showed a strong interaction with very small superparamagnetic iron oxide particles (VSOP), which are used as imaging probes for experimental magnetic resonance imaging (MRI). Hyaluronic acid (HA) represents another negatively charged GAG which is supposed to function as binding motif for VSOP as well. We investigated the effects of Pi on the amounts of HA in cells and EV and studied the HA-dependent interaction between VSOP with cells and EV. Rat VSMC were treated with elevated concentrations of Pi. CKD in rats was induced by adenine feeding. EV were isolated from culture supernatants and rat plasma. We investigated the role of HA in binding VSOP to cells and EV via cell-binding studies, proton relaxometry, and analysis of cellular signaling, genes, proteins, and HA contents. Due to elevated HA contents, VSMC and EV showed an increased interaction with VSOP after Pi stimulation. Amongst others, Pi induced hyaluronan synthase (HAS)2 expression and activation of the Wnt pathway in VSMC. An alternative upregulation of HA by iloprost and an siRNA-mediated knockdown of HAS2 confirmed the importance of HA in cells and EV for VSOP binding. The in vitro-derived data were validated by analyses of plasma-derived EV from uremic rats. In conclusion, the inorganic uremic toxin Pi induces HA synthesis in cells and EV, which leads to an increased interaction with VSOP. HA might therefore be a potential molecular target structure for improved detection of pathologic tissue changes secondary to CKD like atherosclerosis or cardiomyopathy using EV, VSOP and MRI.<\/jats:p>","DOI":"10.3390\/ijms25052571","type":"journal-article","created":{"date-parts":[[2024,2,22]],"date-time":"2024-02-22T11:28:47Z","timestamp":1708601327000},"page":"2571","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Inorganic Phosphate-Induced Extracellular Vesicles from Vascular Smooth Muscle Cells Contain Elevated Levels of Hyaluronic Acid, Which Enhance Their Interaction with Very Small Superparamagnetic Iron Oxide Particles"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2602-226X","authenticated-orcid":false,"given":"Christian","family":"Freise","sequence":"first","affiliation":[{"name":"Department of Radiology, Campus Mitte, Charit\u00e9\u2014Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin and Humboldt-Universit\u00e4t zu Berlin, Charit\u00e9platz 1, 10117 Berlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karina","family":"Biskup","sequence":"additional","affiliation":[{"name":"Institute of Diagnostic Laboratory Medicine, Clinical Chemistry and Pathobiochemistry, Campus Virchow-Klinikum, Charit\u00e9\u2014Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin and Humboldt-Universit\u00e4t zu Berlin, Augustenburger Platz 1, 13353 Berlin, Germany"},{"name":"Department of Human Medicine, Medical School Berlin, R\u00fcdesheimer Str. 50, 14197 Berlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"V\u00e9ronique","family":"Blanchard","sequence":"additional","affiliation":[{"name":"Institute of Diagnostic Laboratory Medicine, Clinical Chemistry and Pathobiochemistry, Campus Virchow-Klinikum, Charit\u00e9\u2014Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin and Humboldt-Universit\u00e4t zu Berlin, Augustenburger Platz 1, 13353 Berlin, Germany"},{"name":"Department of Human Medicine, Medical School Berlin, R\u00fcdesheimer Str. 50, 14197 Berlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9819-3060","authenticated-orcid":false,"given":"J\u00f6rg","family":"Schnorr","sequence":"additional","affiliation":[{"name":"Department of Radiology, Campus Mitte, Charit\u00e9\u2014Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin and Humboldt-Universit\u00e4t zu Berlin, Charit\u00e9platz 1, 10117 Berlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2994-8263","authenticated-orcid":false,"given":"Matthias","family":"Taupitz","sequence":"additional","affiliation":[{"name":"Department of Radiology, Campus Mitte, Charit\u00e9\u2014Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin and Humboldt-Universit\u00e4t zu Berlin, Charit\u00e9platz 1, 10117 Berlin, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,2,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1053\/j.jrn.2007.10.007","article-title":"Phosphate is a uremic toxin","volume":"18","author":"Burke","year":"2008","journal-title":"J. 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