title: Role of Indoxyl Sulfate as a Predisposing Factor for Atrial Fibrillation in Renal Dysfunction.
abstract: BACKGROUND
  Renal dysfunction is a major risk factor for atrial fibrillation (AF). The uremic toxin indoxyl sulfate may contribute to the progression of cardiac fibrosis and AF substrate in renal dysfunction.
  
  
  RESULTS
  Male Sprague-Dawley rats were assigned randomly to the following groups: 5/6 nephrectomy (5/6Nx) with vehicle, 5/6Nx with AST-120, sham procedure with vehicle, and sham procedure with AST-120. Vehicle and AST-120 were administered for 4 weeks. Serum levels of IS were significantly increased in 5/6Nx groups. Expression of malondialdehyde, an indicator of oxidative stress, was upregulated in the left atrium of 5/6Nx groups and was accompanied by an increase in expression of NADPH oxidase 2 and 4. Monocyte-mediated inflammatory signals such as CD68, monocyte chemoattractant protein 1, and vascular cell adhesion molecule 1 were also upregulated in 5/6Nx groups. Interstitial fibrosis was promoted heterogeneously, and expression of profibrotic indicators such as transforming growth factor β1, α-smooth muscle actin, and collagen type 1 was upregulated in left atrium tissue of 5/6Nx groups. In cultured atrial fibroblasts, incubation with IS upregulated expression of the markers of oxidative stress, inflammation, and profibrotic factors. These results suggest the direct effects of IS on the progression of AF substrate. AF was consistently and invariably induced by atrial extrastimuli in 5/6Nx groups in electrophysiological experiments. AST-120 treatment significantly alleviated renal dysfunction-induced oxidative stress, inflammation, and atrial fibrosis and, consequently, attenuated AF inducibility.
  
  
  CONCLUSIONS
  Indoxyl sulfate facilitates atrial fibrosis and AF and thus is a novel therapeutic target for prevention of renal dysfunction-induced AF.
authors.affiliation: Department of Endocrinology, Metabolism, Rheumatology and Nephrology, Oita University Faculty of Medicine, Oita, Japan (K.A., N.F., T.N., H.S.).
authors.forename: Kohei
authors.initials: K
authors.lastname: Aoki
authors.affiliation: Department of Cardiology and Clinical Examination, Oita University Faculty of Medicine, Oita, Japan (Y.T., H.K., S.S., A.F., N.T.).
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Teshima
authors.affiliation: Department of Cardiology and Clinical Examination, Oita University Faculty of Medicine, Oita, Japan (Y.T., H.K., S.S., A.F., N.T.).
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Kondo
authors.affiliation: Department of Cardiology and Clinical Examination, Oita University Faculty of Medicine, Oita, Japan (Y.T., H.K., S.S., A.F., N.T.).
authors.forename: Shotaro
authors.initials: S
authors.lastname: Saito
authors.affiliation: Department of Cardiology and Clinical Examination, Oita University Faculty of Medicine, Oita, Japan (Y.T., H.K., S.S., A.F., N.T.).
authors.forename: Akira
authors.initials: A
authors.lastname: Fukui
authors.affiliation: Department of Endocrinology, Metabolism, Rheumatology and Nephrology, Oita University Faculty of Medicine, Oita, Japan (K.A., N.F., T.N., H.S.).
authors.forename: Naoya
authors.initials: N
authors.lastname: Fukunaga
authors.affiliation: Department of Endocrinology, Metabolism, Rheumatology and Nephrology, Oita University Faculty of Medicine, Oita, Japan (K.A., N.F., T.N., H.S.).
authors.forename: Tomoko
authors.initials: T
authors.lastname: Nawata
authors.affiliation: College of Judo Therapy and Acupuncture-Moxibustion, Oita Medical Technology School, Oita, Japan (T.S.).
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Shimada
authors.affiliation: Department of Cardiology and Clinical Examination, Oita University Faculty of Medicine, Oita, Japan (Y.T., H.K., S.S., A.F., N.T.).
authors.forename: Naohiko
authors.initials: N
authors.lastname: Takahashi
authors.affiliation: Department of Endocrinology, Metabolism, Rheumatology and Nephrology, Oita University Faculty of Medicine, Oita, Japan (K.A., N.F., T.N., H.S.).
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Shibata
mesh_terms: D000818:Animals; D001281:Atrial Fibrillation / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D015415:Biomarkers / Q000378:metabolism; D002244:Carbon / Q000494:pharmacology; D002304:Cardiac Pacing, Artificial; D002478:Cells, Cultured; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism / Q000648:ultrastructure; D005347:Fibroblasts / Q000378:metabolism / Q000648:ultrastructure; D005355:Fibrosis; D007200:Indican / Q000378:metabolism* / Q000494:pharmacology; D018836:Inflammation Mediators / Q000378:metabolism; D007668:Kidney / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D009206:Myocardium / Q000378:metabolism / Q000648:ultrastructure; D009392:Nephrectomy; D018384:Oxidative Stress; D010087:Oxides / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D012307:Risk Factors; D015398:Signal Transduction; D013997:Time Factors; D014511:Uremia / Q000150:complications* / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology
chemical_list: D015415:Biomarkers; D018836:Inflammation Mediators; D010087:Oxides; D002244:Carbon; C040896:AST 120; D007200:Indican
keywords: atrial fibrillation; indoxyl sulfate; renal dysfunction