{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T15:51:26Z","timestamp":1793116286266,"version":"4.5.0"},"reference-count":64,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2025,4,25]],"date-time":"2025-04-25T00:00:00Z","timestamp":1745539200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["372486779 (SFB 1340\/2)"],"award-info":[{"award-number":["372486779 (SFB 1340\/2)"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxins"],"abstract":"<jats:p>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-\u03baB. 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\u2013matrix axis.<\/jats:p>","DOI":"10.3390\/toxins17050217","type":"journal-article","created":{"date-parts":[[2025,4,25]],"date-time":"2025-04-25T08:57:47Z","timestamp":1745571467000},"page":"217","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"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 \u201cGut\u2013Matrix Axis\u201d"],"prefix":"10.3390","volume":"17","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, 10117 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanne","family":"Metzkow","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, 10117 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Zappe","sequence":"additional","affiliation":[{"name":"Department of Biology, Chemistry and Pharmacy, Freie Universit\u00e4t Berlin, 14195 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8795-8507","authenticated-orcid":false,"given":"Monika","family":"Ebert","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, 10117 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3012-1810","authenticated-orcid":false,"given":"Nicola","family":"Stolzenburg","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, 10117 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6732-1560","authenticated-orcid":false,"given":"Julia","family":"Hahndorf","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, 10117 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"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, 10117 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Pagel","sequence":"additional","affiliation":[{"name":"Department of Biology, Chemistry and Pharmacy, Freie Universit\u00e4t Berlin, 14195 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"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, 10117 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1186\/s13073-016-0296-x","article-title":"Microbial metabolism of dietary components to bioactive metabolites: Opportunities for new therapeutic interventions","volume":"8","author":"Zhang","year":"2016","journal-title":"Genome Med."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Six, I., Flissi, N., Lenglet, G., Louvet, L., Kamel, S., Gallet, M., Massy, Z.A., and Liabeuf, S. (2020). Uremic Toxins and Vascular Dysfunction. Toxins, 12.","DOI":"10.3390\/toxins12060404"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Lim, Y.J., Sidor, N.A., Tonial, N.C., Che, A., and Urquhart, B.L. (2021). Uremic Toxins in the Progression of Chronic Kidney Disease and Cardiovascular Disease: Mechanisms and Therapeutic Targets. Toxins, 13.","DOI":"10.3390\/toxins13020142"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1159\/000077536","article-title":"Oral ADSORBENT AST-120 decreases carotid intima-media thickness and arterial stiffness in patients with chronic renal failure","volume":"27","author":"Nakamura","year":"2004","journal-title":"Kidney Blood Press. Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1897","DOI":"10.1681\/ASN.2013101062","article-title":"The uremic toxicity of indoxyl sulfate and p-cresyl sulfate: A systematic review","volume":"25","author":"Vanholder","year":"2014","journal-title":"J. Am. Soc. Nephrol. JASN"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.trsl.2021.10.001","article-title":"Gut microbial metabolite TMAO increases peritoneal inflammation and peritonitis risk in peritoneal dialysis patients","volume":"240","author":"Zhang","year":"2022","journal-title":"Transl. Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2627","DOI":"10.1161\/CIRCULATIONAHA.105.553198","article-title":"Relation between serum phosphate level and cardiovascular event rate in people with coronary disease","volume":"112","author":"Tonelli","year":"2005","journal-title":"Circulation"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Cancela, A.L., Santos, R.D., Titan, S.M., Goldenstein, P.T., Rochitte, C.E., Lemos, P.A., dos Reis, L.M., Graciolli, F.G., Jorgetti, V., and Moys\u00e9s, R.M. (2012). Phosphorus is associated with coronary artery disease in patients with preserved renal function. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0036883"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1398","DOI":"10.2215\/CJN.03150318","article-title":"Characteristics of Colon-Derived Uremic Solutes","volume":"13","author":"Mair","year":"2018","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1230","DOI":"10.1016\/j.kint.2020.01.028","article-title":"Gut microbiota generation of protein-bound uremic toxins and related metabolites is not altered at different stages of chronic kidney disease","volume":"97","author":"Gryp","year":"2020","journal-title":"Kidney Int."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"431","DOI":"10.2215\/CJN.03600807","article-title":"Endotoxemia is related to systemic inflammation and atherosclerosis in peritoneal dialysis patients","volume":"3","author":"Szeto","year":"2008","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"133","DOI":"10.2215\/CJN.04610510","article-title":"Circulating endotoxemia: A novel factor in systemic inflammation and cardiovascular disease in chronic kidney disease","volume":"6","author":"McIntyre","year":"2011","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1159\/000381990","article-title":"The Gut as a Source of Inflammation in Chronic Kidney Disease","volume":"130","author":"Lau","year":"2015","journal-title":"Nephron"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Popkov, V.A., Zharikova, A.A., Demchenko, E.A., Andrianova, N.V., Zorov, D.B., and Plotnikov, E.Y. (2022). Gut Microbiota as a Source of Uremic Toxins. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23010483"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1007\/s11906-023-01263-3","article-title":"Gut Microbiota and Its Role in the Brain-Gut-Kidney Axis in Hypertension","volume":"25","author":"Vallianou","year":"2023","journal-title":"Curr. Hypertens. Rep."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Nie, H.Y., Ge, J., Huang, G.X., Liu, K.G., Yue, Y., Li, H., Lin, H.G., Zhang, T., Yan, H.F., and Xu, B.X. (2024). New insights into the intestinal barrier through \u201cgut-organ\u201d axes and a glimpse of the microgravity\u2019s effects on intestinal barrier. Front. Physiol., 15.","DOI":"10.3389\/fphys.2024.1465649"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"5602","DOI":"10.1111\/jcmm.16572","article-title":"Uraemic extracellular vesicles augment osteogenic transdifferentiation of vascular smooth muscle cells via enhanced AKT signalling and PiT-1 expression","volume":"25","author":"Freise","year":"2021","journal-title":"J. Cell. Mol. Med."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Freise, C., Zappe, A., L\u00f6wa, N., Schnorr, J., Pagel, K., Wiekhorst, F., and Taupitz, M. (2023). Uremic Toxin-Induced Exosome-like Extracellular Vesicles Contain Enhanced Levels of Sulfated Glycosaminoglycans which Facilitate the Interaction with Very Small Superparamagnetic Iron Oxide Particles. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241814253"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Freise, C., Biskup, K., Blanchard, V., Schnorr, J., and Taupitz, M. (2024). 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. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25052571"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1093\/glycob\/cwy003","article-title":"Keratan sulfate, a complex glycosaminoglycan with unique functional capability","volume":"28","author":"Caterson","year":"2018","journal-title":"Glycobiology"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.matbio.2019.02.002","article-title":"Hyaluronan biology: A complex balancing act of structure, function, location and context","volume":"78\u201379","author":"Garantziotis","year":"2019","journal-title":"Matrix Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"9152","DOI":"10.1021\/acs.chemrev.8b00354","article-title":"Proteoglycan Chemical Diversity Drives Multifunctional Cell Regulation and Therapeutics","volume":"118","author":"Karamanos","year":"2018","journal-title":"Chem. Rev."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2921","DOI":"10.1111\/febs.14830","article-title":"Insight into the role of chondroitin sulfate E in angiogenesis","volume":"286","author":"Kastana","year":"2019","journal-title":"FEBS J."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2935","DOI":"10.1074\/jbc.R111.298430","article-title":"Chondroitin sulfate \u201cwobble motifs\u201d modulate maintenance and differentiation of neural stem cells and their progeny","volume":"287","author":"Purushothaman","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1030","DOI":"10.1038\/nature05817","article-title":"Heparan sulphate proteoglycans fine-tune mammalian physiology","volume":"446","author":"Bishop","year":"2007","journal-title":"Nature"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1038\/nature14581","article-title":"Glypican-1 identifies cancer exosomes and detects early pancreatic cancer","volume":"523","author":"Melo","year":"2015","journal-title":"Nature"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Proudfoot, A.E.I., Johnson, Z., Bonvin, P., and Handel, T.M. (2017). Glycosaminoglycan Interactions with Chemokines Add Complexity to a Complex System. Pharmaceuticals, 10.","DOI":"10.3390\/ph10030070"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Lara-Prado, J.I., Pazos-P\u00e9rez, F., M\u00e9ndez-Landa, C.E., Grajales-Garc\u00eda, D.P., Feria-Ram\u00edrez, J.A., Salazar-Gonz\u00e1lez, J.J., Cruz-Romero, M., and Trevi\u00f1o-Becerra, A. (2021). Acute Kidney Injury and Organ Dysfunction: What Is the Role of Uremic Toxins?. Toxins, 13.","DOI":"10.3390\/toxins13080551"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/S0090-4295(94)80005-7","article-title":"Identification of a mucin layer in the urinary bladder","volume":"44","author":"Grist","year":"1994","journal-title":"Urology"},{"key":"ref_30","unstructured":"Suvarna, S.K., Layton, C., and Bancroft, J.D. (2013). 12\u2014Carbohydrates. Bancroft\u2019s Theory and Practice of Histological Techniques, Churchill Livingstone. [7th ed.]."},{"key":"ref_31","first-page":"289","article-title":"Demonstration of all connective tissue elements in a single section; pentachrome stains","volume":"60","author":"Movat","year":"1955","journal-title":"AMA Arch. Pathol."},{"key":"ref_32","unstructured":"Lillie, R.D. (1965). Histopathologic Technic and Practical Histochemistry, Blakiston Division, McGraw-Hill."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1016\/S0959-440X(00)00125-1","article-title":"Recent advances in the study of the biosynthesis and functions of sulfated glycosaminoglycans","volume":"10","author":"Sugahara","year":"2000","journal-title":"Curr. Opin. Struct. Biol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1006\/jmbi.2000.4261","article-title":"Molecular Cloning and Expression of Human UDP-d-Xylose: Proteoglycan Core Protein \u03b2-d-Xylosyltransferase and its First Isoform XT-II","volume":"304","author":"Kuhn","year":"2000","journal-title":"J. Mol. Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1016\/S0959-437X(97)80153-0","article-title":"The sulfatase gene family","volume":"7","author":"Parenti","year":"1997","journal-title":"Curr. Opin. Genet. Dev."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"241","DOI":"10.3109\/00365598409180189","article-title":"The aortic content of glycosaminoglycans, hydroxyproline and calcium in experimental uraemia with special reference to parathyroidectomy and vitamin-D treatment","volume":"18","author":"Krog","year":"1984","journal-title":"Scand. J. Urol. Nephrol."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Liew, H., Roberts, M.A., Pope, A., and McMahon, L.P. (2021). Endothelial glycocalyx damage in kidney disease correlates with uraemic toxins and endothelial dysfunction. BMC Nephrol., 22.","DOI":"10.1186\/s12882-020-02219-4"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"e651","DOI":"10.1002\/mco2.651","article-title":"Endothelial dysfunction: Molecular mechanisms and clinical implications","volume":"5","author":"Wang","year":"2024","journal-title":"MedComm"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Foudi, N., Palayer, M., Briet, M., and Garnier, A.S. (2021). Arterial Remodelling in Chronic Kidney Disease: Impact of Uraemic Toxins and New Pharmacological Approaches. J. Clin. Med., 10.","DOI":"10.3390\/jcm10173803"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/S0076-6879(06)16006-1","article-title":"Comprehensive enzymatic characterization of glycosyltransferases with a beta3GT or beta4GT motif","volume":"416","author":"Togayachi","year":"2006","journal-title":"Methods Enzymol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"11396","DOI":"10.1074\/jbc.M707549200","article-title":"Identification of chondroitin sulfate glucuronyltransferase as chondroitin synthase-3 involved in chondroitin polymerization: Chondroitin polymerization is achieved by multiple enzyme complexes consisting of chondroitin synthase family members","volume":"283","author":"Izumikawa","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"21075","DOI":"10.1074\/jbc.M002101200","article-title":"Molecular cloning and expression of a novel chondroitin 6-O-sulfotransferase","volume":"275","author":"Kitagawa","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1136\/jim-2019-001156","article-title":"Metformin decreases hyaluronan synthesis by vascular smooth muscle cells","volume":"68","author":"Sainio","year":"2020","journal-title":"J. Investig. Med."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Golusda, L., K\u00fchl, A.A., Lehmann, M., Dahlke, K., Mueller, S., Boehm-Sturm, P., Saatz, J., Traub, H., Schnorr, J., and Freise, C. (2022). Visualization of Inflammation in Experimental Colitis by Magnetic Resonance Imaging Using Very Small Superparamagnetic Iron Oxide Particles. Front. Physiol., 13.","DOI":"10.3389\/fphys.2022.862212"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1007\/s12079-018-0495-x","article-title":"Transforming growth factor-\u03b21 mediated CHST11 and CHSY1 mRNA expression is ROS dependent in vascular smooth muscle cells","volume":"13","author":"Mohamed","year":"2019","journal-title":"J. Cell Commun. Signal."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"38738","DOI":"10.1074\/jbc.M111.247981","article-title":"Endothelial surface N-glycans mediate monocyte adhesion and are targets for anti-inflammatory effects of peroxisome proliferator-activated receptor \u03b3 ligands","volume":"286","author":"Chacko","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1172\/JCI1604","article-title":"Proinflammatory stimuli regulate endothelial hyaluronan expression and CD44\/HA-dependent primary adhesion","volume":"101","author":"Mohamadzadeh","year":"1998","journal-title":"J. Clin. Investig."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1016\/S0006-291X(05)81529-3","article-title":"Vascular smooth muscle cells exhibit increased growth in response to elevated glucose","volume":"187","author":"Natarajan","year":"1992","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1370","DOI":"10.1161\/01.CIR.99.10.1370","article-title":"Antioxidants improve impaired insulin-mediated glucose uptake and prevent migration and proliferation of cultured rabbit coronary smooth muscle cells induced by high glucose","volume":"99","author":"Yasunari","year":"1999","journal-title":"Circulation"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"H736","DOI":"10.1152\/ajpheart.00935.2009","article-title":"Diabetic conditions promote binding of monocytes to vascular smooth muscle cells and their subsequent differentiation","volume":"298","author":"Meng","year":"2010","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1116","DOI":"10.1007\/s10495-017-1392-0","article-title":"Acquisition of anoikis resistance promotes alterations in the Ras\/ERK and PI3K\/Akt signaling pathways and matrix remodeling in endothelial cells","volume":"22","author":"Nader","year":"2017","journal-title":"Apoptosis Int. J. Program. Cell Death"},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Toyoda, S., Shin, J., Fukuhara, A., Otsuki, M., and Shimomura, I. (2022). Transforming growth factor \u03b21 signaling links extracellular matrix remodeling to intracellular lipogenesis upon physiological feeding events. J. Biol. Chem., 298.","DOI":"10.1016\/j.jbc.2022.101748"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"2000","DOI":"10.1002\/jemt.23369","article-title":"Indoxyl sulfate-induced calcification of vascular smooth muscle cells via the PI3K\/Akt\/NF-\u03baB signaling pathway","volume":"82","author":"He","year":"2019","journal-title":"Microsc. Res. Tech."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1536\/ihj.22-603","article-title":"Trimethylamine N-oxide Promotes Atherosclerosis by Regulating Low-Density Lipoprotein-Induced Autophagy in Vascular Smooth Muscle Cells Through PI3K\/AKT\/mTOR Pathway","volume":"64","author":"Shi","year":"2023","journal-title":"Int. Heart J."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Kapetanaki, S., Kumawat, A.K., Persson, K., and Demirel, I. (2021). The Fibrotic Effects of TMAO on Human Renal Fibroblasts Is Mediated by NLRP3, Caspase-1 and the PERK\/Akt\/mTOR Pathway. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222111864"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1424","DOI":"10.1002\/ijc.22862","article-title":"Activation of PI3K-Akt signaling pathway promotes prostate cancer cell invasion","volume":"121","author":"Shukla","year":"2007","journal-title":"Int. J. Cancer"},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Zhang, H., and Sun, S.C. (2015). NF-\u03baB in inflammation and renal diseases. Cell Biosci., 5.","DOI":"10.1186\/s13578-015-0056-4"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1993","DOI":"10.1093\/ndt\/gfae090","article-title":"Both partial inactivation as well as activation of NF-\u03baB signaling lead to hypertension and chronic kidney disease","volume":"39","author":"Zhang","year":"2024","journal-title":"Nephrol. Dial Transpl."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Poveda, J., Tabara, L.C., Fernandez-Fernandez, B., Martin-Cleary, C., Sanz, A.B., Selgas, R., Ortiz, A., and Sanchez-Ni\u00f1o, M.D. (2013). TWEAK\/Fn14 and Non-Canonical NF-kappaB Signaling in Kidney Disease. Front. Immunol., 4.","DOI":"10.3389\/fimmu.2013.00447"},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Lindner, M., Laporte, A., Elomaa, L., Lee-Thedieck, C., Olmer, R., and Weinhart, M. (2022). Flow-induced glycocalyx formation and cell alignment of HUVECs compared to iPSC-derived ECs for tissue engineering applications. Front. Cell Dev. Biol., 10.","DOI":"10.3389\/fcell.2022.953062"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1083\/jcb.50.1.172","article-title":"The smooth muscle cell. II. Growth of smooth muscle in culture and formation of elastic fibers","volume":"50","author":"Ross","year":"1971","journal-title":"J. Cell Biol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1934","DOI":"10.1046\/j.1523-1755.2003.00924.x","article-title":"Review on uremic toxins: Classification, concentration, and interindividual variability","volume":"63","author":"Vanholder","year":"2003","journal-title":"Kidney Int."},{"key":"ref_63","unstructured":"Farhat, Y. (2022, July 25). PicoGreen Cell Proliferation Assay Protocol. Available online: http:\/\/protocol-place.com."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1111\/apha.12400","article-title":"The lignan (+)-episesamin interferes with TNF-\u03b1-induced activation of VSMC via diminished activation of NF-\u0138B, ERK1\/2 and AKT and decreased activity of gelatinases","volume":"213","author":"Freise","year":"2015","journal-title":"Acta Physiol."}],"container-title":["Toxins"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6651\/17\/5\/217\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:21:37Z","timestamp":1760030497000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6651\/17\/5\/217"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,25]]},"references-count":64,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2025,5]]}},"alternative-id":["toxins17050217"],"URL":"https:\/\/doi.org\/10.3390\/toxins17050217","relation":{},"ISSN":["2072-6651"],"issn-type":[{"value":"2072-6651","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,25]]}}}