{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T05:51:35Z","timestamp":1790833895673,"version":"4.1.0"},"reference-count":46,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2024,3,20]],"date-time":"2024-03-20T00:00:00Z","timestamp":1710892800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J Cellular Molecular Medi"],"published-print":{"date-parts":[[2024,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>In the last decade, extensive attention has been paid to the uremic toxin indoxyl sulphate (IS) as an inducer of cardiac fibroblast (cFib) activation and cardiac fibrosis in chronic kidney disease. At cellular level, IS engages aryl hydrocarbon receptor (AhR) and regulates many biological functions. We analysed how AhR inhibition by CH\u2010223191 (CH) and overexpression of non\u2010functional (dominant negative, DN) nuclear factor\u2010erythroid\u20102\u2010related factor 2 (NRF2), a transcription factor recruited by AhR, modulate the response of neonatal mouse (nm) cFib to IS. We also evaluated nm\u2010cardiomyocytes after incubation with the conditioned medium (CM) of IS\u00b1CH\u2010treated nm\u2010cFib. IS induced activation, collagen synthesis, TLR4 and\u2013downstream\u2013MCP\u20101, and the genes encoding angiotensinogen, angiotensin\u2010converting enzyme, angiotensin type 1 receptor (<jats:italic>AT1r<\/jats:italic>) and neprilysin (<jats:italic>Nepr<\/jats:italic>) in nm\u2010cFib. CH antagonized IS\u2010initiated nm\u2010cFib activation, but did not affect or even magnified the other features. IS promoted NRF2 nuclear translocation and expression the NRF2 target <jats:italic>Nqo1<\/jats:italic>. Both pre\u2010incubation with CH and transfection of DN\u2010NRF2 resulted in loss of NRF2 nuclear localization. Moreover, DN\u2010NRF2 overexpression led to greater TLR4 and MCP\u20101 levels following exposure to IS. The CM of IS\u2010primed nm\u2010cFib and to a larger extent the CM of IS+CH\u2010treated nm\u2010cFib upregulated <jats:italic>AT1r<\/jats:italic>, <jats:italic>Nepr<\/jats:italic> and TNF\u03b1 and myostatin genes in nm\u2010cardiomyocytes. Hence, IS triggers pro\u2010inflammatory activation of nm\u2010cFib partly via AhR, and AhR\u2010NRF2 counteract it. Strategies other than AhR inhibition are needed to target IS detrimental actions on cardiac cells.<\/jats:p>","DOI":"10.1111\/jcmm.18192","type":"journal-article","created":{"date-parts":[[2024,3,20]],"date-time":"2024-03-20T05:15:13Z","timestamp":1710911713000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Indoxyl sulphate\u2010initiated activation of cardiac fibroblasts is modulated by aryl hydrocarbon receptor and nuclear factor\u2010erythroid\u20102\u2010related factor 2"],"prefix":"10.1111","volume":"28","author":[{"given":"Chiara","family":"Barisione","sequence":"first","affiliation":[{"name":"Department of Surgical and Integrated Diagnostic Sciences University of Genova  Genova Italy"},{"name":"Cardiac, Thoracic and Vascular Department IRCCS Ospedale Policlinico San Martino  Genova 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