{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T21:04:10Z","timestamp":1789592650480,"version":"build-2803163510"},"reference-count":50,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2021,12,18]],"date-time":"2021-12-18T00:00:00Z","timestamp":1639785600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP16H05114"],"award-info":[{"award-number":["JP16H05114"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP20H03406"],"award-info":[{"award-number":["JP20H03406"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxins"],"abstract":"<jats:p>Activation of mTORC1 (mechanistic target of rapamycin complex 1) in renal tissue has been reported in chronic kidney disease (CKD)-induced renal fibrosis. However, the molecular mechanisms responsible for activating mTORC1 in CKD pathology are not well understood. The purpose of this study was to identify the uremic toxin involved in mTORC1-induced renal fibrosis. Among the seven protein-bound uremic toxins, only indoxyl sulfate (IS) caused significant activation of mTORC1 in human kidney 2 cells (HK-2 cells). This IS-induced mTORC1 activation was inhibited in the presence of an organic anion transporter inhibitor, a NADPH oxidase inhibitor, and an antioxidant. IS also induced epithelial\u2013mesenchymal transition of tubular epithelial cells (HK-2 cells), differentiation of fibroblasts into myofibroblasts (NRK-49F cells), and inflammatory response of macrophages (THP-1 cells), which are associated with renal fibrosis, and these effects were inhibited in the presence of rapamycin (mTORC1 inhibitor). In in vivo experiments, IS overload was found to activate mTORC1 in the mouse kidney. The administration of AST-120 or rapamycin targeted to IS or mTORC1 ameliorated renal fibrosis in Adenine-induced CKD mice. The findings reported herein indicate that IS activates mTORC1, which then contributes to renal fibrosis. Therapeutic interventions targeting IS and mTORC1 could be effective against renal fibrosis in CKD.<\/jats:p>","DOI":"10.3390\/toxins13120909","type":"journal-article","created":{"date-parts":[[2021,12,20]],"date-time":"2021-12-20T02:40:32Z","timestamp":1639968032000},"page":"909","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":56,"title":["Indoxyl Sulfate Contributes to mTORC1-Induced Renal Fibrosis via The OAT\/NADPH Oxidase\/ROS Pathway"],"prefix":"10.3390","volume":"13","author":[{"given":"Takehiro","family":"Nakano","sequence":"first","affiliation":[{"name":"Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 8620973, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9268-4144","authenticated-orcid":false,"given":"Hiroshi","family":"Watanabe","sequence":"additional","affiliation":[{"name":"Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 8620973, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tadashi","family":"Imafuku","sequence":"additional","affiliation":[{"name":"Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 8620973, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Tokumaru","sequence":"additional","affiliation":[{"name":"Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 8620973, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Issei","family":"Fujita","sequence":"additional","affiliation":[{"name":"Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 8620973, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nanaka","family":"Arimura","sequence":"additional","affiliation":[{"name":"Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 8620973, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hitoshi","family":"Maeda","sequence":"additional","affiliation":[{"name":"Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 8620973, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Motoko","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Akebono Clinic, Kumamoto 8614112, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazutaka","family":"Matsushita","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Akebono Clinic, Kumamoto 8614112, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7832-2339","authenticated-orcid":false,"given":"Masafumi","family":"Fukagawa","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Endocrinology and Metabolism, Tokai University School of Medicine, Kanagawa 2591193, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toru","family":"Maruyama","sequence":"additional","affiliation":[{"name":"Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 8620973, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1038\/s41581-019-0248-y","article-title":"Targeting the progression of chronic kidney disease","volume":"16","author":"Lamas","year":"2020","journal-title":"Nat. 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