title: Indoxyl sulfate enhances IL-1β-induced E-selectin expression in endothelial cells in acute kidney injury by the ROS/MAPKs/NFκB/AP-1 pathway.
abstract: Uremic toxins are considered a risk factor for cardiovascular disorders in kidney diseases, but it is not known whether, under inflammatory conditions, they affect adhesion molecule expression on endothelial cells, which may play a critical role in acute kidney injury (AKI). In the present study, in cardiovascular surgery-related AKI patients, who are known to have high plasma levels of the uremic toxin indoxyl sulfate (IS), plasma levels of IL-1β were found to be positively correlated with plasma levels of the adhesion molecule E-selectin. In addition, high E-selectin and IL-1β expression were seen in the kidney of ischemia/reperfusion mice in vivo. We also examined the effects of IS on E-selectin expression by IL-1β-treated human umbilical vein endothelial cells (HUVECs) and the underlying mechanism. IS pretreatment of HUVECs significantly increased IL-1β-induced E-selectin expression, monocyte adhesion, and the phosphorylation of mitogen-activated protein kinases (ERK, p38, and JNK) and transcription factors (NF-κB and AP-1), and phosphorylation was decreased by pretreatment with inhibitors of ERK1/2 (PD98059), p38 MAPK (SB202190), and JNK (SP600125). Furthermore, IS increased IL-1β-induced reactive oxygen species (ROS) production and this effect was inhibited by pretreatment with N-acetylcysteine (a ROS scavenger) or apocynin (a NADPH oxidase inhibitor). Gel shift assays and ChIP-PCR demonstrated that IS enhanced E-selectin expression in IL-1-treated HUVECs by increasing NF-κB and AP-1 DNA-binding activities. Moreover, IS-enhanced E-selectin expression in IL-1β-treated HUVECs was inhibited by Bay11-7082, a NF-κB inhibitor. Thus, IS may play an important role in the development of cardiovascular disorders in kidney diseases during inflammation by increasing endothelial expression of E-selectin.
authors.affiliation: Department of Anatomy and Cell Biology, College of Medicine, National Taiwan University, No. 1, Sec 1, Ren-Ai Road, Taipei, Taiwan.
authors.forename: Wen-Ching
authors.initials: WC
authors.lastname: Shen
authors.affiliation: Department of Anatomy and Cell Biology, College of Medicine, National Taiwan University, No. 1, Sec 1, Ren-Ai Road, Taipei, Taiwan.|Lipid Science and Aging Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan.|Department of Fragrance and Cosmetic Science, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Chan-Jung
authors.initials: CJ
authors.lastname: Liang
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Yun-Lin Branch, National Taiwan University Hospital, Douliou City, Taiwan.
authors.forename: Tao-Ming
authors.initials: TM
authors.lastname: Huang
authors.affiliation: Department of Anatomy and Cell Biology, College of Medicine, National Taiwan University, No. 1, Sec 1, Ren-Ai Road, Taipei, Taiwan.
authors.forename: Chen-Wei
authors.initials: CW
authors.lastname: Liu
authors.affiliation: Department of Anatomy and Cell Biology, College of Medicine, National Taiwan University, No. 1, Sec 1, Ren-Ai Road, Taipei, Taiwan.
authors.forename: Shu-Huei
authors.initials: SH
authors.lastname: Wang
authors.affiliation: Department of Surgery, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan.
authors.forename: Guang-Huar
authors.initials: GH
authors.lastname: Young
authors.affiliation: Department of Family Medicine, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan.
authors.forename: Jaw-Shiun
authors.initials: JS
authors.lastname: Tsai
authors.affiliation: Department of Obstetrics and Gynecology, Hsinchu Cathay General Hospital, Hsinchu, Taiwan.
authors.forename: Ying-Chin
authors.initials: YC
authors.lastname: Tseng
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Far Eastern Memorial Hospital, New Taipei City, Taiwan.
authors.forename: Yu-Sen
authors.initials: YS
authors.lastname: Peng
authors.affiliation: Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University, No. 7, Chung-Shan South Road, Taipei, Taiwan. q91421028@ntu.edu.tw.
authors.forename: Vin-Cent
authors.initials: VC
authors.lastname: Wu
authors.affiliation: Department of Anatomy and Cell Biology, College of Medicine, National Taiwan University, No. 1, Sec 1, Ren-Ai Road, Taipei, Taiwan. ylchenv@ntu.edu.tw.
authors.forename: Yuh-Lien
authors.initials: YL
authors.lastname: Chen
mesh_terms: D058186:Acute Kidney Injury / Q000097:blood / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D000368:Aged; D000818:Animals; D015415:Biomarkers / Q000097:blood / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D019040:E-Selectin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007200:Indican / Q000097:blood / Q000633:toxicity*; D053583:Interleukin-1beta / Q000819:agonists* / Q000378:metabolism; D007668:Kidney / Q000098:blood supply / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress / Q000187:drug effects; D011042:Poisons / Q000097:blood / Q000633:toxicity*; D015427:Reperfusion Injury / Q000097:blood / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D015854:Up-Regulation / Q000187:drug effects*; D014511:Uremia / Q000209:etiology
chemical_list: D015415:Biomarkers; D019040:E-Selectin; C508585:IL1B protein, human; D053583:Interleukin-1beta; D011042:Poisons; C546936:SELE protein, human; D007200:Indican
keywords: Acute kidney injury; E-selectin; Endothelial cells; Indoxyl sulfate; Reactive oxygen species