{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T02:36:45Z","timestamp":1793241405724,"version":"4.5.0"},"reference-count":62,"publisher":"Oxford University Press (OUP)","issue":"11","license":[{"start":{"date-parts":[[2025,6,17]],"date-time":"2025-06-17T00:00:00Z","timestamp":1750118400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/501100008131","name":"University of Bonn","doi-asserted-by":"publisher","award":["2020-1A-06"],"award-info":[{"award-number":["2020-1A-06"]}],"id":[{"id":"10.13039\/501100008131","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008131","name":"University of Bonn","doi-asserted-by":"publisher","award":["2022-1A-05 to PD"],"award-info":[{"award-number":["2022-1A-05 to PD"]}],"id":[{"id":"10.13039\/501100008131","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010578","name":"German Cardiac Society","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100010578","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100016021","name":"Corona-Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100016021","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["397484323\u2013TRR 259"],"award-info":[{"award-number":["397484323\u2013TRR 259"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["514976099"],"award-info":[{"award-number":["514976099"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"name":"German Federal Ministry of Education and Research","award":["01EO2107"],"award-info":[{"award-number":["01EO2107"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,9,29]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Aims<\/jats:title>\n                  <jats:p>Chronic kidney disease (CKD) is closely associated with cardiovascular disease (CVD). This includes aortic valve stenosis (AS), one of the most common valve diseases among adults. CKD leads to the retention of uremic toxins such as indoxyl sulfate (IS), which is known to induce inflammatory and pro-calcific processes. We hypothesize that IS specifically induces AS formation.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods and results<\/jats:title>\n                  <jats:p>Stimulation of human valvular interstitial cells (VICs) with IS in addition to phosphate led to increased calcification. RNA sequencing identified naked cuticle homologue 2 (NKD2) as an up-regulated gene in VICs under uremic conditions. Knockdown of NKD2 reduced calcification of VICs and upregulation of IL-6. The organic anion transporting polypeptide 3A1 (OAT3A1) was identified to mediate IS uptake as well as upregulation of NKD2 and IL-6. We identified NF-\u03baB signalling to be involved in IS-induced IL-6 upregulation. In vivo, we investigated combined models of adenine-induced kidney injury or oral IS supplementation with wire injury-induced AS in C57BL\/6J mice. Echocardiography showed aggravated AS in uremic mice compared with control mice after wire injury. Explanted valves from uremic mice with AS exhibited a significant increase in macrophage infiltration, fibrotic areas and valvular NKD2 expression compared with controls. IS-treated mice showed aggravated AS compared with control mice. This was accompanied by more prominent valve fibrosis, macrophage infiltration, and NKD2 expression in explanted valves of IS-treated mice. In the blood and bone marrow, IS treatment led to the differentiation of monocytes into intermediate and non-classical monocytes. This was paralleled by IS-induced monocyte adhesion to valvular endothelial cells in vitro.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>Uremic conditions aggravate AS development in mice by inducing valvular fibrosis and macrophage infiltration. IS is involved in this process and stimulates monocyte differentiation and adhesion to the valvular endothelium. On a cellular level, we hypothesize that IS-mediated NKD2 induction leads to a calcifying and inflammatory response in VICs.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/cvr\/cvaf106","type":"journal-article","created":{"date-parts":[[2025,6,26]],"date-time":"2025-06-26T15:04:23Z","timestamp":1750950263000},"page":"1734-1749","source":"Crossref","is-referenced-by-count":9,"title":["The role of uremic toxin indoxyl sulfate in the pathophysiology of aortic valve stenosis"],"prefix":"10.1093","volume":"121","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1394-6471","authenticated-orcid":false,"given":"Philip","family":"D\u00fcsing","sequence":"first","affiliation":[{"name":"Department of Internal Medicine II, Heart Center, University Hospital Bonn, Medizinische Klinik und Poliklinik II , Venusberg Campus 1, Bonn 53127 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabel","family":"G\u00f6bel","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine II, Heart Center, University Hospital Bonn, Medizinische Klinik und Poliklinik II , Venusberg Campus 1, Bonn 53127 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6473-2399","authenticated-orcid":false,"given":"Ansgar","family":"Ackerschott","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine II, Heart Center, University Hospital Bonn, Medizinische Klinik und Poliklinik II , Venusberg Campus 1, Bonn 53127 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurine","family":"Reese","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine II, Heart Center, University Hospital Bonn, Medizinische Klinik und Poliklinik II , Venusberg Campus 1, Bonn 53127 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Giavalisco","sequence":"additional","affiliation":[{"name":"Max Planck Institute for Biology of Ageing, Metabolomics Core Facility , Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederik","family":"Dethloff","sequence":"additional","affiliation":[{"name":"Max Planck Institute for Biology of Ageing, Metabolomics Core Facility , Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sven Thomas","family":"Niepmann","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine II, Heart Center, University Hospital Bonn, Medizinische Klinik und Poliklinik II , Venusberg Campus 1, Bonn 53127 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Stei","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine II, Heart Center, University Hospital Bonn, Medizinische Klinik und Poliklinik II , Venusberg Campus 1, Bonn 53127 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Beiert","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine II, Heart Center, University Hospital Bonn, Medizinische Klinik und Poliklinik II , Venusberg Campus 1, Bonn 53127 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1531-2088","authenticated-orcid":false,"given":"Sebastian","family":"Zimmer","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine II, Heart Center, University Hospital Bonn, Medizinische Klinik und Poliklinik II , Venusberg Campus 1, Bonn 53127 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Kurts","sequence":"additional","affiliation":[{"name":"Institute of Molecular Medicine and Experimental Immunology, University of Bonn , Bonn ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georg","family":"Nickenig","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine II, Heart Center, University Hospital Bonn, Medizinische Klinik und Poliklinik II , Venusberg Campus 1, Bonn 53127 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felix","family":"Jansen","sequence":"additional","affiliation":[{"name":"Kardiologie K\u00f6ln, Gemeinschaftspraxis Kardiologie , Cologne ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5759-7627","authenticated-orcid":false,"given":"Andreas","family":"Zietzer","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine II, Heart Center, University Hospital Bonn, Medizinische Klinik und Poliklinik II , Venusberg Campus 1, Bonn 53127 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