{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T19:05:34Z","timestamp":1792695934059,"version":"4.5.0"},"reference-count":92,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2020,10,29]],"date-time":"2020-10-29T00:00:00Z","timestamp":1603929600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxins"],"abstract":"<jats:p>Indoxyl sulfate (IS), a uremic toxin, causes chronic kidney disease (CKD) progression via its tubulotoxicity. After cellular uptake, IS directly induces apoptotic and necrotic cell death of tubular cells. Additionally, IS increases oxidative stress and decreases antioxidant capacity, which are associated with tubulointerstitial injury. Injured tubular cells are a major source of transforming growth factor-\u03b21 (TGF-\u03b21), which induces myofibroblast transition from residual renal cells in damaged kidney, recruits inflammatory cells and thereby promotes extracellular matrix deposition in renal fibrosis. Moreover, IS upregulates signal transducers and activators of transcription 3 phosphorylation, followed by increases in TGF-\u03b21, monocyte chemotactic protein-1 and \u03b1-smooth muscle actin production, which participate in interstitial inflammation, renal fibrosis and, consequently, CKD progression. Clinically, higher serum IS levels are independently associated with renal function decline and predict all-cause mortality in CKD. The poor removal of serum IS in conventional hemodialysis is also significantly associated with all-cause mortality and heart failure incidence in end-stage renal disease patients. Scavenging the IS precursor by AST-120 can markedly reduce tubular IS staining that attenuates renal tubular injury, ameliorates IS-induced oxidative stress and rescues antioxidant glutathione activity in tubular epithelial cells, thereby providing a protective role against tubular injury and ultimately retarding renal function decline.<\/jats:p>","DOI":"10.3390\/toxins12110684","type":"journal-article","created":{"date-parts":[[2020,10,29]],"date-time":"2020-10-29T23:06:12Z","timestamp":1604012772000},"page":"684","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":120,"title":["Indoxyl Sulfate, a Tubular Toxin, Contributes to the Development of Chronic Kidney Disease"],"prefix":"10.3390","volume":"12","author":[{"given":"Tong-Hong","family":"Cheng","sequence":"first","affiliation":[{"name":"School of Medicine, Fu Jen Catholic University, New Taipei 242, Taiwan"},{"name":"Department of Internal Medicine, Taoyuan Armed Forces General Hospital, Taoyuan 325, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming-Chieh","family":"Ma","sequence":"additional","affiliation":[{"name":"School of Medicine, Fu Jen Catholic University, New Taipei 242, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min-Tser","family":"Liao","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Taoyuan Armed Forces General Hospital, Taoyuan 325, Taiwan"},{"name":"Department of Pediatrics, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0370-3951","authenticated-orcid":false,"given":"Cai-Mei","family":"Zheng","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan"},{"name":"Division of Nephrology, Department of Internal Medicine, Taipei Medical University Shuang Ho Hospital, New Taipei 235, Taiwan"},{"name":"Taipei Medical University-Research Center of Urology and Kidney, Taipei Medical University, Taipei 110, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7062-8560","authenticated-orcid":false,"given":"Kuo-Cheng","family":"Lu","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Medicine, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei 231, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chun-Hou","family":"Liao","sequence":"additional","affiliation":[{"name":"School of Medicine, Fu Jen Catholic University, New Taipei 242, Taiwan"},{"name":"Divisions of Urology, Department of Surgery, Cardinal Tien Hospital, New Taipei 23148, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Chou","family":"Hou","sequence":"additional","affiliation":[{"name":"School of Medicine, Fu Jen Catholic University, New Taipei 242, Taiwan"},{"name":"Division of Nephrology, Department of Medicine, Cardinal-Tien Hospital, School of Medicine, Fu-Jen Catholic University, New Taipei 234, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen-Chih","family":"Liu","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Medicine, Taipei Hospital, Ministry of Health and Welfare, New Taipei 242, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9452-5179","authenticated-orcid":false,"given":"Chien-Lin","family":"Lu","sequence":"additional","affiliation":[{"name":"School of Medicine, Fu Jen Catholic University, New Taipei 242, Taiwan"},{"name":"Division of Nephrology, Department of Medicine, Fu Jen Catholic University Hospital, New Taipei 242, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,10,29]]},"reference":[{"key":"ref_1","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_2","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1159\/000353764","article-title":"Chronic kidney disease causes disruption of gastric and small intestinal epithelial tight junction","volume":"38","author":"Vaziri","year":"2013","journal-title":"Am. J. Nephrol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1093\/ndt\/gfv095","article-title":"Altered intestinal microbial flora and impaired epithelial barrier structure and function in CKD: The nature, mechanisms, consequences and potential treatment","volume":"31","author":"Vaziri","year":"2016","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Gryp, T., Huys, G.R.B., Joossens, M., Van Biesen, W., Glorieux, G., and Vaneechoutte, M. (2020). Isolation and Quantification of Uremic Toxin Precursor-Generating Gut Bacteria in Chronic Kidney Disease Patients. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21061986"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1007\/BF03190428","article-title":"Sulfation of indoxyl by human and rat aryl (phenol) sulfotransferases to form indoxyl sulfate","volume":"27","author":"Banoglu","year":"2002","journal-title":"Eur. J. Drug Metab. Pharmacokinet."},{"key":"ref_6","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_7","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1007\/BF03226377","article-title":"Hepatic microsomal metabolism of indole to indoxyl, a precursor of indoxyl sulfate","volume":"26","author":"Banoglu","year":"2001","journal-title":"Eur. J. Drug Metab. Pharmacokinet."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1208\/s12248-012-9413-y","article-title":"Renal organic anion transporters (SLC22 family): Expression, regulation, roles in toxicity, and impact on injury and disease","volume":"15","author":"Wang","year":"2013","journal-title":"AAPS J."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"4939","DOI":"10.1038\/s41598-017-04949-2","article-title":"Key Role for the Organic Anion Transporters, OAT1 and OAT3, in the in vivo Handling of Uremic Toxins and Solutes","volume":"7","author":"Wu","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1508","DOI":"10.2215\/CJN.00300113","article-title":"Renal clearance and intestinal generation of p-cresyl sulfate and indoxyl sulfate in CKD","volume":"8","author":"Poesen","year":"2013","journal-title":"Clin. J. Am. Soc. Nephrol. CJASN"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1016\/j.jfda.2018.10.008","article-title":"Measuring serum total and free indoxyl sulfate and p-cresyl sulfate in chronic kidney disease using UPLC-MS\/MS","volume":"27","author":"Lin","year":"2019","journal-title":"J. Food Drug Anal."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1711","DOI":"10.1097\/01.ASN.0000022017.96399.B2","article-title":"Role of Organic Anion Transporters in the Tubular Transport of Indoxyl Sulfate and the Induction of its Nephrotoxicity","volume":"13","author":"Enomoto","year":"2002","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Hatakeyama, S., Yamamoto, H., Okamoto, A., Imanishi, K., Tokui, N., Okamoto, T., Suzuki, Y., Sugiyama, N., Imai, A., and Kudo, S. (2012). Effect of an Oral Adsorbent, AST-120, on Dialysis Initiation and Survival in Patients with Chronic Kidney Disease. Int. J. Nephrol., 376128.","DOI":"10.1155\/2012\/376128"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1080\/0886022X.2018.1561376","article-title":"Review of the efficacy of AST-120 (KREMEZIN(\u00ae)) on renal function in chronic kidney disease patients","volume":"41","author":"Asai","year":"2019","journal-title":"Ren. Fail."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1080\/15569543.2016.1222442","article-title":"Methods of reducing the level of indoxyl sulfate\u2014One of the most potent protein-bound uremic toxins","volume":"35","author":"Karbowska","year":"2016","journal-title":"Toxin Rev."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1159\/000346628","article-title":"Very low protein diet reduces indoxyl sulfate levels in chronic kidney disease","volume":"35","author":"Marzocco","year":"2013","journal-title":"Blood Purif."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1038\/ki.2010.539","article-title":"Low-protein diet supplemented with ketoacids reduces the severity of renal disease in 5\/6 nephrectomized rats: A role for KLF15","volume":"79","author":"Gao","year":"2011","journal-title":"Kidney Int."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"223","DOI":"10.2215\/CJN.05240515","article-title":"Synbiotics Easing Renal Failure by Improving Gut Microbiology (SYNERGY): A Randomized Trial","volume":"11","author":"Rossi","year":"2016","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"23389","DOI":"10.1038\/srep23389","article-title":"Improved dialytic removal of protein-bound uraemic toxins with use of albumin binding competitors: An in vitro human whole blood study","volume":"6","author":"Tao","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1016\/j.taap.2013.04.029","article-title":"JBP485 improves gentamicin-induced acute renal failure by regulating the expression and function of Oat1 and Oat3 in rats","volume":"271","author":"Guo","year":"2013","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Akiyama, Y., Kikuchi, K., Saigusa, D., Suzuki, T., Takeuchi, Y., Mishima, E., Yamamoto, Y., Ishida, A., Sugawara, D., and Jinno, D. (2013). Indoxyl sulfate down-regulates SLCO4C1 transporter through up-regulation of GATA3. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0066518"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Sternkopf, M., Thor\u00f6e-Boveleth, S., Beck, T., Oleschko, K., Erlenk\u00f6tter, A., Tschulena, U., Steppan, S., Speer, T., Goettsch, C., and Jankowski, V. (2019). A Bifunctional Adsorber Particle for the Removal of Hydrophobic Uremic Toxins from Whole Blood of Renal Failure Patients. Toxins, 11.","DOI":"10.3390\/toxins11070389"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1093\/ckj\/sfv069","article-title":"Pathophysiological role of different tubular epithelial cell death modes in acute kidney injury","volume":"8","year":"2015","journal-title":"Clin. Kidney J."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"9","DOI":"10.2169\/internalmedicine.43.9","article-title":"Mechanisms of Tubulointerstitial Injury in the Kidney: Final Common Pathways to End-stage Renal Failure","volume":"43","author":"Nangaku","year":"2004","journal-title":"Intern. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1038\/nrneph.2015.3","article-title":"Mechanisms of maladaptive repair after AKI leading to accelerated kidney ageing and CKD","volume":"11","author":"Ferenbach","year":"2015","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1681\/ASN.2007080913","article-title":"Acute tubular necrosis is a syndrome of physiologic and pathologic dissociation","volume":"19","author":"Rosen","year":"2008","journal-title":"J. Am. Soc. Nephrol. JASN"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Lu, C.-L., Liao, C.-H., Lu, K.-C., and Ma, M.-C. (2020). TRPV1 Hyperfunction Involved in Uremic Toxin Indoxyl Sulfate-Mediated Renal Tubular Damage. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21176212"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1177\/0192623318768171","article-title":"Indoxyl Sulfate Induces Apoptosis and Hypertrophy in Human Kidney Proximal Tubular Cells","volume":"46","author":"Ellis","year":"2018","journal-title":"Toxicol. Pathol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"488","DOI":"10.1038\/labinvest.2011.194","article-title":"Indoxyl sulfate-induced epithelial-to-mesenchymal transition and apoptosis of renal tubular cells as novel mechanisms of progression of renal disease","volume":"92","author":"Kim","year":"2012","journal-title":"Lab. Investig."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1773","DOI":"10.1093\/ndt\/15.11.1773","article-title":"An oral sorbent reduces overload of indoxyl sulphate and gene expression of TGF-beta1 in uraemic rat kidneys","volume":"15","author":"Miyazaki","year":"2000","journal-title":"Nephrol. Dial. Transpl."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1159\/000064108","article-title":"An oral adsorbent downregulates renal expression of genes that promote interstitial inflammation and fibrosis in diabetic rats","volume":"92","author":"Aoyama","year":"2002","journal-title":"Nephron"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"S4","DOI":"10.1038\/ki.2008.516","article-title":"Oxidative stress and inflammation, a link between chronic kidney disease and cardiovascular disease","volume":"74","author":"Cachofeiro","year":"2008","journal-title":"Kidney Int. Suppl."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1446","DOI":"10.2337\/db08-0057","article-title":"Oxidative stress as a major culprit in kidney disease in diabetes","volume":"57","author":"Forbes","year":"2008","journal-title":"Diabetes"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"F461","DOI":"10.1152\/ajprenal.90735.2008","article-title":"Reactive oxygen species\/oxidative stress contributes to progression of kidney fibrosis following transient ischemic injury in mice","volume":"297","author":"Kim","year":"2009","journal-title":"Am. J. Physiol. Ren. Physiol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.biocel.2006.07.001","article-title":"Free radicals and antioxidants in normal physiological functions and human disease","volume":"39","author":"Valko","year":"2007","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"118","DOI":"10.4103\/0973-7847.70902","article-title":"Free radicals, antioxidants and functional foods: Impact on human health","volume":"4","author":"Lobo","year":"2010","journal-title":"Pharmacogn. Rev."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1089\/ars.2016.6665","article-title":"Oxidant Mechanisms in Renal Injury and Disease","volume":"25","author":"Ratliff","year":"2016","journal-title":"Antioxid. Redox Signal."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"8010","DOI":"10.1073\/pnas.130135897","article-title":"Identification of renox, an NAD(P)H oxidase in kidney","volume":"97","author":"Geiszt","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1038\/ki.2012.434","article-title":"Nox4 as a potential therapeutic target for treatment of uremic toxicity associated to chronic kidney disease","volume":"83","author":"Gorin","year":"2013","journal-title":"Kidney Int."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1671","DOI":"10.1046\/j.1523-1755.2003.00906.x","article-title":"Uremic toxins of organic anions up-regulate PAI-1 expression by induction of NF-\u03baB and free radical in proximal tubular cells","volume":"63","author":"Motojima","year":"2003","journal-title":"Kidney Int."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"C685","DOI":"10.1152\/ajpcell.00236.2012","article-title":"CREB, NF-\u03baB, and NADPH oxidase coordinately upregulate indoxyl sulfate-induced angiotensinogen expression in proximal tubular cells","volume":"304","author":"Shimizu","year":"2013","journal-title":"Am. J. Physiol. Physiol."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Bolati, D., Shimizu, H., Yisireyili, M., Nishijima, F., and Niwa, T. (2013). Indoxyl sulfate, a uremic toxin, downregulates renal expression of Nrf2 through activation of NF-\u03baB. BMC Nephrol., 14.","DOI":"10.1186\/1471-2369-14-56"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Edamatsu, T., Fujieda, A., and Itoh, Y. (2018). Phenyl sulfate, indoxyl sulfate and p-cresyl sulfate decrease glutathione level to render cells vulnerable to oxidative stress in renal tubular cells. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0193342"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2747","DOI":"10.1681\/ASN.V12122747","article-title":"Oxidative stress and endothelial function in chronic renal failure","volume":"12","author":"Annuk","year":"2001","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1016\/j.jdiacomp.2013.07.005","article-title":"Association of biomarkers of inflammation and oxidative stress with the risk of chronic kidney disease in Type 2 diabetes mellitus in North Indian population","volume":"27","author":"Gupta","year":"2013","journal-title":"J. Diabetes Complicat."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1016\/j.arcmed.2014.04.002","article-title":"Protein-bound uremic toxins, inflammation and oxidative stress: A cross-sectional study in stage 3-4 chronic kidney disease","volume":"45","author":"Rossi","year":"2014","journal-title":"Arch. Med. Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1303","DOI":"10.1681\/ASN.2008080844","article-title":"Reduction of renal superoxide dismutase in progressive diabetic nephropathy","volume":"20","author":"Fujita","year":"2009","journal-title":"J. Am. Soc. Nephrol. JASN"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2447","DOI":"10.1681\/ASN.2014060613","article-title":"Extracellular Superoxide Dismutase Protects against Proteinuric Kidney Disease","volume":"26","author":"Tan","year":"2015","journal-title":"J. Am. Soc. Nephrol. JASN"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1543","DOI":"10.1089\/ars.2017.7207","article-title":"Extracellular Superoxide Dismutase Attenuates Renal Oxidative Stress Through the Activation of Adenosine Monophosphate-Activated Protein Kinase in Diabetic Nephropathy","volume":"28","author":"Hong","year":"2018","journal-title":"Antioxid. Redox Signal."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1159\/000112823","article-title":"Indoxyl sulfate reduces superoxide scavenging activity in the kidneys of normal and uremic rats","volume":"28","author":"Owada","year":"2008","journal-title":"Am. J. Nephrol."},{"key":"ref_51","first-page":"48","article-title":"Indoxyl sulfate-lowering capacity of oral sorbents affects the prognosis of kidney function and oxidative stress in chronic kidney disease","volume":"17","author":"Taki","year":"2007","journal-title":"J. Ren. Nutr. Off. J. Counc. Ren. Nutr. Natl. Kidney Found."},{"key":"ref_52","first-page":"2089","article-title":"Oral charcoal adsorbent (AST-120) prevents progression of cardiac damage in chronic kidney disease through suppression of oxidative stress","volume":"24","author":"Fujii","year":"2009","journal-title":"Nephrol. Dial. Transplant. Off. Publ. Eur. Dial. Transpl. Assoc. Eur. Ren. Assoc."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1016\/j.metabol.2010.01.023","article-title":"Oral adsorbent AST-120 ameliorates tubular injury in chronic renal failure patients by reducing proteinuria and oxidative stress generation","volume":"60","author":"Nakamura","year":"2011","journal-title":"Metab. Clin. Exp."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"30","DOI":"10.2215\/CJN.05340610","article-title":"Indoxyl sulfate-induced endothelial dysfunction in patients with chronic kidney disease via an induction of oxidative stress","volume":"6","author":"Yu","year":"2011","journal-title":"Clin. J. Am. Soc. Nephrol. CJASN"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1681\/ASN.2008121226","article-title":"New insights into epithelial-mesenchymal transition in kidney fibrosis","volume":"21","author":"Liu","year":"2010","journal-title":"J. Am. Soc. Nephrol. JASN"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"i37","DOI":"10.1093\/ndt\/gft267","article-title":"Transforming growth factor-\u03b2 and the progression of renal disease","volume":"29","author":"Loeffler","year":"2013","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1159\/000449511","article-title":"Renal Interstitial Fibrosis: An Imperfect Predictor of Kidney Disease Progression in Some Patient Cohorts","volume":"44","author":"Lee","year":"2016","journal-title":"Am. J. Nephrol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"2301","DOI":"10.1046\/j.1523-1755.2000.00414.x","article-title":"Antibody to transforming growth factor-beta ameliorates tubular apoptosis in unilateral ureteral obstruction","volume":"58","author":"Miyajima","year":"2000","journal-title":"Kidney Int."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Isaka, Y. (2018). Targeting TGF-\u03b2 Signaling in Kidney Fibrosis. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19092532"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1007\/978-981-13-8871-2_12","article-title":"Myofibroblast in Kidney Fibrosis: Origin, Activation, and Regulation","volume":"1165","author":"Yuan","year":"2019","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1038\/cr.2008.328","article-title":"Non-Smad pathways in TGF-beta signaling","volume":"19","author":"Zhang","year":"2009","journal-title":"Cell Res."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"F545","DOI":"10.1152\/ajprenal.00120.2009","article-title":"Expression patterns of connective tissue growth factor and of TGF-\u03b2 isoforms during glomerular injury recapitulate glomerulogenesis","volume":"299","author":"Ito","year":"2010","journal-title":"Am. J. Physiol. Physiol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1038\/ki.2009.297","article-title":"Transforming growth factor-beta2 upregulates sphingosine kinase-1 activity, which in turn attenuates the fibrotic response to TGF-beta2 by impeding CTGF expression","volume":"76","author":"Ren","year":"2009","journal-title":"Kidney Int."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1016\/j.semnephrol.2012.04.001","article-title":"How does TGF-\u03b2 mediate tubulointerstitial fibrosis?","volume":"32","author":"Gewin","year":"2012","journal-title":"Semin Nephrol."},{"key":"ref_65","first-page":"S15","article-title":"Indoxyl sulfate increases the gene expressions of TGF-beta 1, TIMP-1 and pro-alpha 1(I) collagen in uremic rat kidneys","volume":"62","author":"Miyazaki","year":"1997","journal-title":"Kidney Int. Suppl."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/j.lfs.2012.11.012","article-title":"Indoxyl sulfate upregulates renal expression of ICAM-1 via production of ROS and activation of NF-\u03baB and p53 in proximal tubular cells","volume":"92","author":"Shimizu","year":"2013","journal-title":"Life Sci."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2019\/2050183","article-title":"Indoxyl Sulfate Induces Renal Fibroblast Activation through a Targetable Heat Shock Protein 90-Dependent Pathway","volume":"2019","author":"Milanesi","year":"2019","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"3690","DOI":"10.1681\/ASN.2015091014","article-title":"Stat3 Controls Tubulointerstitial Communication during CKD","volume":"27","author":"Muorah","year":"2016","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1038\/ki.2010.158","article-title":"JAK\/STAT signaling in renal diseases","volume":"78","author":"Chuang","year":"2010","journal-title":"Kidney Int."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1159\/000341515","article-title":"Stat3 contributes to indoxyl sulfate-induced inflammatory and fibrotic gene expression and cellular senescence","volume":"36","author":"Shimizu","year":"2012","journal-title":"Am. J. Nephrol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1007\/s004670050289","article-title":"Urinary transforming growth factor-beta in patients with glomerular diseases","volume":"11","author":"Murakami","year":"1997","journal-title":"Pediatr Nephrol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1053\/j.ajkd.2005.12.036","article-title":"A multicenter, randomized, double-blind, placebo-controlled, dose-ranging study of AST-120 (Kremezin) in patients with moderate to severe CKD","volume":"47","author":"Schulman","year":"2006","journal-title":"Am. J. Kidney Dis. Off. J. Natl. Kidney Found."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1159\/000013594","article-title":"Oral adsorbent AST-120 ameliorates interstitial fibrosis and transforming growth factor-beta(1) expression in spontaneously diabetic (OLETF) rats","volume":"20","author":"Aoyama","year":"2000","journal-title":"Am. J. Nephrol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1096\/fasebj.1.4.3308611","article-title":"The glomerular mesangial cell: An expanding role for a specialized pericyte","volume":"1","author":"Schlondorff","year":"1987","journal-title":"Faseb J."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1337","DOI":"10.1016\/j.addr.2010.08.011","article-title":"Mesangial pathology in glomerular disease: Targets for therapeutic intervention","volume":"62","author":"Scindia","year":"2010","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1179","DOI":"10.1681\/ASN.2008050549","article-title":"The mesangial cell revisited: No cell is an island","volume":"20","author":"Banas","year":"2009","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_77","first-page":"1","article-title":"Indoxyl Sulfate Induces Mesangial Cell Proliferation via the Induction of COX-2","volume":"2016","author":"Li","year":"2016","journal-title":"Mediat. Inflamm."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"F1551","DOI":"10.1152\/ajprenal.00281.2004","article-title":"Indoxyl sulfate induces complex redox alterations in mesangial cells","volume":"290","author":"Gelasco","year":"2006","journal-title":"Am. J. Physiol. Ren. Physiol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"637","DOI":"10.2131\/jts.39.637","article-title":"Indoxyl sulfate induces renin release and apoptosis of kidney mesangial cells","volume":"39","author":"Wang","year":"2014","journal-title":"J. Toxicol. Sci."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"876","DOI":"10.1681\/ASN.2013121283","article-title":"The cardiovascular effect of the uremic solute indole-3 acetic acid","volume":"26","author":"Dou","year":"2015","journal-title":"J. Am. Soc. Nephrol. JASN"},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Liabeuf, S., Laville, S.M., Glorieux, G., Cheddani, L., Brazier, F., Titeca Beauport, D., Valholder, R., Choukroun, G., and Massy, Z.A. (2020). Difference in Profiles of the Gut-Derived Tryptophan Metabolite Indole Acetic Acid between Transplanted and Non-Transplanted Patients with Chronic Kidney Disease. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21062031"},{"key":"ref_82","first-page":"938","article-title":"p-Cresyl sulphate and indoxyl sulphate predict progression of chronic kidney disease","volume":"26","author":"Wu","year":"2011","journal-title":"Nephrol. Dial. Transplant. Off. Publ. Eur. Dial. Transpl. Assoc. Eur. Ren. Assoc."},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Wang, W., Hao, G., Pan, Y., Ma, S., Yang, T., Shi, P., Zhu, Q., Xie, Y., Ma, S., and Zhang, Q. (2019). Serum indoxyl sulfate is associated with mortality in hospital-acquired acute kidney injury: A prospective cohort study. BMC Nephrol., 20.","DOI":"10.1186\/s12882-019-1238-9"},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Menez, S., Hanouneh, M., Shafi, T., and Jaar, B.G. (2019). Indoxyl sulfate is associated with mortality after AKI\u2014More evidence needed!. BMC Nephrol., 20.","DOI":"10.1186\/s12882-019-1465-0"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1841","DOI":"10.1007\/s00216-012-5929-3","article-title":"Protein-bound uremic toxins in hemodialysis patients measured by liquid chromatography\/tandem mass spectrometry and their effects on endothelial ROS production","volume":"403","author":"Itoh","year":"2012","journal-title":"Anal. Bioanal Chem."},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Yamamoto, S., Fuller, D.S., Komaba, H., Nomura, T., Massy, Z.A., Bieber, B., Robinson, B., Pisoni, R., and Fukagawa, M. (2020). Serum total indoxyl sulfate and clinical outcomes in hemodialysis patients: Results from the Japan Dialysis Outcomes and Practice Patterns Study. Clin. Kidney J.","DOI":"10.1093\/ckj\/sfaa121"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"111","DOI":"10.2215\/CJN.04730514","article-title":"Association of indoxyl sulfate with heart failure among patients on hemodialysis","volume":"10","author":"Cao","year":"2015","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1254","DOI":"10.1681\/ASN.2015010068","article-title":"Serum Indoxyl Sulfate Associates with Postangioplasty Thrombosis of Dialysis Grafts","volume":"27","author":"Wu","year":"2016","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1551","DOI":"10.2215\/CJN.03980609","article-title":"Serum indoxyl sulfate is associated with vascular disease and mortality in chronic kidney disease patients","volume":"4","author":"Barreto","year":"2009","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1780","DOI":"10.1038\/sj.ki.5000340","article-title":"Indoxyl sulfate stimulates proliferation of rat vascular smooth muscle cells","volume":"69","author":"Yamamoto","year":"2006","journal-title":"Kidney Int."},{"key":"ref_91","doi-asserted-by":"crossref","unstructured":"Lano, G., Burtey, S., and Sall\u00e9e, M. (2020). Indoxyl Sulfate, a Uremic Endotheliotoxin. Toxins, 12.","DOI":"10.3390\/toxins12040229"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"722","DOI":"10.1253\/circj.CJ-15-0949","article-title":"Levels of Indoxyl Sulfate in Kidney Transplant Patients, and the Relationship With Hard Outcomes","volume":"80","author":"Liabeuf","year":"2016","journal-title":"Circ. 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