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Indoxyl sulfate enhances IL-1β-induced E-selectin expression in endothelial cells in acute kidney injury by the ROS/MAPKs/NFκB/AP-1 pathway

  • Organ Toxicity and Mechanisms
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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.

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Acknowledgments

This work was supported by a research grant from the National Science Council (NSC 102-2628-B-002-001-MY3).

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    Authors and Affiliations

    1. Department of Anatomy and Cell Biology, College of Medicine, National Taiwan University, No. 1, Sec 1, Ren-Ai Road, Taipei, Taiwan

      Wen-Ching Shen, Chan-Jung Liang, Chen-Wei Liu, Shu-Huei Wang & Yuh-Lien Chen

    2. Division of Nephrology, Department of Internal Medicine, Yun-Lin Branch, National Taiwan University Hospital, Douliou City, Taiwan

      Tao-Ming Huang

    3. Department of Surgery, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan

      Guang-Huar Young

    4. Department of Family Medicine, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan

      Jaw-Shiun Tsai

    5. Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University, No. 7, Chung-Shan South Road, Taipei, Taiwan

      Vin-Cent Wu

    6. Department of Obstetrics and Gynecology, Hsinchu Cathay General Hospital, Hsinchu, Taiwan

      Ying-Chin Tseng

    7. Division of Nephrology, Department of Internal Medicine, Far Eastern Memorial Hospital, New Taipei City, Taiwan

      Yu-Sen Peng

    8. Lipid Science and Aging Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan

      Chan-Jung Liang

    9. Department of Fragrance and Cosmetic Science, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan

      Chan-Jung Liang

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    Wen-Ching Shen and Chan-Jung Liang have contributed equally to this study.

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    Shen, WC., Liang, CJ., Huang, TM. et al. Indoxyl sulfate enhances IL-1β-induced E-selectin expression in endothelial cells in acute kidney injury by the ROS/MAPKs/NFκB/AP-1 pathway. Arch Toxicol 90, 2779–2792 (2016). https://doi.org/10.1007/s00204-015-1652-0

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