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Endothelial Microparticles in Uremia: Biomarkers and Potential Therapeutic Targets
Open AccessArticle

Indoxyl Sulfate Stimulates Angiogenesis by Regulating Reactive Oxygen Species Production via CYP1B1

1
Department of Nephrology and Hypertension, DIGD, UMC Utrecht, University of Utrecht, 3584 CX Utrecht, The Netherlands
2
Department of Cardiology, Division Heart & Lungs, UMC Utrecht, University of Utrecht, 3584 CX Utrecht, The Netherlands
3
Regenerative Medicine Utrecht, UMC Utrecht, University of Utrecht, 3584 CX Utrecht, The Netherlands
4
Department of Physiology, Amsterdam UMC, VUmc location, Amsterdam Cardiovascular Science, 1081 HV Amsterdam, The Netherlands
5
Department of Pathology, UMC Utrecht, University of Utrecht, 3584 CX Utrecht, The Netherlands
6
Department of Cardiology, Erasmus MC, 3015 GD Rotterdam, The Netherlands
7
Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, London NW1 2DA, UK
8
Health Data Research UK and Institute of Health Informatics, University College London, London NW1 2DA, UK
9
Department of Clinical Chemistry and Heamatology, University of Utrecht, 3584 CX Utrecht, The Netherlands
10
Division of Paediatrics, UMC Utrecht, University of Utrecht, 3584 CX Utrecht, The Netherlands
*
Author to whom correspondence should be addressed.
Toxins 2019, 11(8), 454; https://doi.org/10.3390/toxins11080454
Received: 14 June 2019 / Revised: 22 July 2019 / Accepted: 29 July 2019 / Published: 2 August 2019
(This article belongs to the Special Issue The Endothelial Effects of Uremic Toxins)
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Abstract

Indoxyl sulfate (IS) is an accumulative protein-bound uremic toxin found in patients with kidney disease. It is reported that IS impairs the vascular endothelium, but a comprehensive overview of all mechanisms active in IS-injury currently remains lacking. Here we performed RNA sequencing in human umbilical vein endothelial cells (HUVECs) after IS or control medium treatment and identified 1293 genes that were affected in a IS-induced response. Gene enrichment analysis highlighted pathways involved in altered vascular formation and cell metabolism. We confirmed these transcriptome profiles at the functional level by demonstrating decreased viability and increased cell senescence in response to IS treatment. In line with the additional pathways highlighted by the transcriptome analysis, we further could demonstrate that IS exposure of HUVECs promoted tubule formation as shown by the increase in total tubule length in a 3D HUVECs/pericytes co-culture assay. Notably, the pro-angiogenic response of IS and increased ROS production were abolished when CYP1B1, one of the main target genes that was highly upregulated by IS, was silenced. This observation indicates IS-induced ROS in endothelial cells is CYP1B1-dependent. Taken together, our findings demonstrate that IS promotes angiogenesis and CYP1B1 is an important factor in IS-activated angiogenic response. View Full-Text
Keywords: indoxyl sulfate; chronic kidney disease; reactive oxygen species; CYP1B1; angiogenesis indoxyl sulfate; chronic kidney disease; reactive oxygen species; CYP1B1; angiogenesis
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MDPI and ACS Style

Pei, J.; Juni, R.; Harakalova, M.; Duncker, D.J.; Asselbergs, F.W.; Koolwijk, P.; van Hinsbergh, V.; Verhaar, M.C.; Mokry, M.; Cheng, C. Indoxyl Sulfate Stimulates Angiogenesis by Regulating Reactive Oxygen Species Production via CYP1B1. Toxins 2019, 11, 454.

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