Indoxyl sulfate stimulates angiogenesis by regulating reactive oxygen species production via CYP1B1

Jiayi Pei, Rio Juni, Magdalena Harakalova, Dirk J. Duncker, Folkert W. Asselbergs, Pieter Koolwijk, Victor van Hinsbergh, Marianne C. Verhaar, Michal Mokry, Caroline Cheng

Research output: Contribution to journalArticleAcademicpeer-review

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.
Original languageEnglish
Article number454
JournalToxins
Volume11
Issue number8
DOIs
Publication statusPublished - 2019

Cite this

Pei, Jiayi ; Juni, Rio ; Harakalova, Magdalena ; Duncker, Dirk J. ; Asselbergs, Folkert W. ; Koolwijk, Pieter ; van Hinsbergh, Victor ; Verhaar, Marianne C. ; Mokry, Michal ; Cheng, Caroline. / Indoxyl sulfate stimulates angiogenesis by regulating reactive oxygen species production via CYP1B1. In: Toxins. 2019 ; Vol. 11, No. 8.
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title = "Indoxyl sulfate stimulates angiogenesis by regulating reactive oxygen species production via CYP1B1",
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.",
author = "Jiayi Pei and Rio Juni and Magdalena Harakalova and Duncker, {Dirk J.} and Asselbergs, {Folkert W.} and Pieter Koolwijk and {van Hinsbergh}, Victor and Verhaar, {Marianne C.} and Michal Mokry and Caroline Cheng",
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Pei, J, Juni, R, Harakalova, M, Duncker, DJ, Asselbergs, FW, Koolwijk, P, van Hinsbergh, V, Verhaar, MC, Mokry, M & Cheng, C 2019, 'Indoxyl sulfate stimulates angiogenesis by regulating reactive oxygen species production via CYP1B1' Toxins, vol. 11, no. 8, 454. https://doi.org/10.3390/toxins11080454

Indoxyl sulfate stimulates angiogenesis by regulating reactive oxygen species production via CYP1B1. / Pei, Jiayi; Juni, Rio; Harakalova, Magdalena; Duncker, Dirk J.; Asselbergs, Folkert W.; Koolwijk, Pieter; van Hinsbergh, Victor; Verhaar, Marianne C.; Mokry, Michal; Cheng, Caroline.

In: Toxins, Vol. 11, No. 8, 454, 2019.

Research output: Contribution to journalArticleAcademicpeer-review

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T1 - Indoxyl sulfate stimulates angiogenesis by regulating reactive oxygen species production via CYP1B1

AU - Pei, Jiayi

AU - Juni, Rio

AU - Harakalova, Magdalena

AU - Duncker, Dirk J.

AU - Asselbergs, Folkert W.

AU - Koolwijk, Pieter

AU - van Hinsbergh, Victor

AU - Verhaar, Marianne C.

AU - Mokry, Michal

AU - Cheng, Caroline

PY - 2019

Y1 - 2019

N2 - 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.

AB - 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.

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