Pro-Arrhythmic Potential of Accumulated Uremic Toxins Is Mediated via Vulnerability of Action Potential Repolarization

Willem B van Ham; Carlijn M Cornelissen; Elizaveta Polyakova; Stephanie M van der Voorn; Merel L Ligtermoet; Jantine Monshouwer-Kloots; Marc A Vos; Alexandre Bossu; Eva van Rooij; Marcel A G van der Heyden; Toon A B van Veen

doi:10.3390/ijms24065373

Pro-Arrhythmic Potential of Accumulated Uremic Toxins Is Mediated via Vulnerability of Action Potential Repolarization

Willem B van Ham, Carlijn M Cornelissen, Elizaveta Polyakova, Stephanie M van der Voorn, Merel L Ligtermoet, Jantine Monshouwer-Kloots, Marc A Vos, Alexandre Bossu, Eva van Rooij, Marcel A G van der Heyden, Toon A B van Veen^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

Chronic kidney disease (CKD) is represented by a diminished filtration capacity of the kidneys. End-stage renal disease patients need dialysis treatment to remove waste and toxins from the circulation. However, endogenously produced uremic toxins (UTs) cannot always be filtered during dialysis. UTs are among the CKD-related factors that have been linked to maladaptive and pathophysiological remodeling of the heart. Importantly, 50% of the deaths in dialysis patients are cardiovascular related, with sudden cardiac death predominating. However, the mechanisms responsible remain poorly understood. The current study aimed to assess the vulnerability of action potential repolarization caused by exposure to pre-identified UTs at clinically relevant concentrations. We exposed human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and HEK293 chronically (48 h) to the UTs indoxyl sulfate, kynurenine, or kynurenic acid. We used optical and manual electrophysiological techniques to assess action potential duration (APD) in the hiPSC-CMs and recorded I Kr currents in stably transfected HEK293 cells (HEK-hERG). Molecular analysis of K V11.1, the ion channel responsible for I Kr, was performed to further understand the potential mechanism underlying the effects of the UTs. Chronic exposure to the UTs resulted in significant APD prolongation. Subsequent assessment of the repolarization current I Kr, often most sensitive and responsible for APD alterations, showed decreased current densities after chronic exposure to the UTs. This outcome was supported by lowered protein levels of K V11.1. Finally, treatment with an activator of the I Kr current, LUF7244, could reverse the APD prolongation, indicating the potential modulation of electrophysiological effects caused by these UTs. This study highlights the pro-arrhythmogenic potential of UTs and reveals a mode of action by which they affect cardiac repolarization.

Original language	English
Article number	5373
Journal	International Journal of Molecular Sciences
Volume	24
Issue number	6
DOIs	https://doi.org/10.3390/ijms24065373
Publication status	Published - 11 Mar 2023

Keywords

K 11.1
cardiac repolarization
cellular electrophysiology
chronic kidney disease
uremic toxins

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10.3390/ijms24065373Licence: CC BY

ijms-24-05373-v2Final published version, 1.47 MBLicence: CC BY

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van Ham, W. B., Cornelissen, C. M., Polyakova, E., van der Voorn, S. M., Ligtermoet, M. L., Monshouwer-Kloots, J., Vos, M. A., Bossu, A., van Rooij, E., van der Heyden, M. A. G., & van Veen, T. A. B. (2023). Pro-Arrhythmic Potential of Accumulated Uremic Toxins Is Mediated via Vulnerability of Action Potential Repolarization. International Journal of Molecular Sciences, 24(6), Article 5373. https://doi.org/10.3390/ijms24065373

@article{d126212843d3483784ce231e36e13239,

title = "Pro-Arrhythmic Potential of Accumulated Uremic Toxins Is Mediated via Vulnerability of Action Potential Repolarization",

abstract = "Chronic kidney disease (CKD) is represented by a diminished filtration capacity of the kidneys. End-stage renal disease patients need dialysis treatment to remove waste and toxins from the circulation. However, endogenously produced uremic toxins (UTs) cannot always be filtered during dialysis. UTs are among the CKD-related factors that have been linked to maladaptive and pathophysiological remodeling of the heart. Importantly, 50% of the deaths in dialysis patients are cardiovascular related, with sudden cardiac death predominating. However, the mechanisms responsible remain poorly understood. The current study aimed to assess the vulnerability of action potential repolarization caused by exposure to pre-identified UTs at clinically relevant concentrations. We exposed human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and HEK293 chronically (48 h) to the UTs indoxyl sulfate, kynurenine, or kynurenic acid. We used optical and manual electrophysiological techniques to assess action potential duration (APD) in the hiPSC-CMs and recorded I Kr currents in stably transfected HEK293 cells (HEK-hERG). Molecular analysis of K V11.1, the ion channel responsible for I Kr, was performed to further understand the potential mechanism underlying the effects of the UTs. Chronic exposure to the UTs resulted in significant APD prolongation. Subsequent assessment of the repolarization current I Kr, often most sensitive and responsible for APD alterations, showed decreased current densities after chronic exposure to the UTs. This outcome was supported by lowered protein levels of K V11.1. Finally, treatment with an activator of the I Kr current, LUF7244, could reverse the APD prolongation, indicating the potential modulation of electrophysiological effects caused by these UTs. This study highlights the pro-arrhythmogenic potential of UTs and reveals a mode of action by which they affect cardiac repolarization. ",

keywords = "K 11.1, cardiac repolarization, cellular electrophysiology, chronic kidney disease, uremic toxins",

author = "{van Ham}, {Willem B} and Cornelissen, {Carlijn M} and Elizaveta Polyakova and {van der Voorn}, {Stephanie M} and Ligtermoet, {Merel L} and Jantine Monshouwer-Kloots and Vos, {Marc A} and Alexandre Bossu and {van Rooij}, Eva and {van der Heyden}, {Marcel A G} and {van Veen}, {Toon A B}",

note = "Publisher Copyright: {\textcopyright} 2023 by the authors.",

year = "2023",

month = mar,

day = "11",

doi = "10.3390/ijms24065373",

language = "English",

volume = "24",

journal = "International Journal of Molecular Sciences",

issn = "1422-0067",

publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",

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van Ham, WB, Cornelissen, CM, Polyakova, E, van der Voorn, SM, Ligtermoet, ML, Monshouwer-Kloots, J, Vos, MA, Bossu, A, van Rooij, E , van der Heyden, MAG & van Veen, TAB 2023, 'Pro-Arrhythmic Potential of Accumulated Uremic Toxins Is Mediated via Vulnerability of Action Potential Repolarization', International Journal of Molecular Sciences, vol. 24, no. 6, 5373. https://doi.org/10.3390/ijms24065373

TY - JOUR

T1 - Pro-Arrhythmic Potential of Accumulated Uremic Toxins Is Mediated via Vulnerability of Action Potential Repolarization

AU - van Ham, Willem B

AU - Cornelissen, Carlijn M

AU - Polyakova, Elizaveta

AU - van der Voorn, Stephanie M

AU - Ligtermoet, Merel L

AU - Monshouwer-Kloots, Jantine

AU - Vos, Marc A

AU - Bossu, Alexandre

AU - van Rooij, Eva

AU - van der Heyden, Marcel A G

AU - van Veen, Toon A B

PY - 2023/3/11

Y1 - 2023/3/11

N2 - Chronic kidney disease (CKD) is represented by a diminished filtration capacity of the kidneys. End-stage renal disease patients need dialysis treatment to remove waste and toxins from the circulation. However, endogenously produced uremic toxins (UTs) cannot always be filtered during dialysis. UTs are among the CKD-related factors that have been linked to maladaptive and pathophysiological remodeling of the heart. Importantly, 50% of the deaths in dialysis patients are cardiovascular related, with sudden cardiac death predominating. However, the mechanisms responsible remain poorly understood. The current study aimed to assess the vulnerability of action potential repolarization caused by exposure to pre-identified UTs at clinically relevant concentrations. We exposed human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and HEK293 chronically (48 h) to the UTs indoxyl sulfate, kynurenine, or kynurenic acid. We used optical and manual electrophysiological techniques to assess action potential duration (APD) in the hiPSC-CMs and recorded I Kr currents in stably transfected HEK293 cells (HEK-hERG). Molecular analysis of K V11.1, the ion channel responsible for I Kr, was performed to further understand the potential mechanism underlying the effects of the UTs. Chronic exposure to the UTs resulted in significant APD prolongation. Subsequent assessment of the repolarization current I Kr, often most sensitive and responsible for APD alterations, showed decreased current densities after chronic exposure to the UTs. This outcome was supported by lowered protein levels of K V11.1. Finally, treatment with an activator of the I Kr current, LUF7244, could reverse the APD prolongation, indicating the potential modulation of electrophysiological effects caused by these UTs. This study highlights the pro-arrhythmogenic potential of UTs and reveals a mode of action by which they affect cardiac repolarization.

AB - Chronic kidney disease (CKD) is represented by a diminished filtration capacity of the kidneys. End-stage renal disease patients need dialysis treatment to remove waste and toxins from the circulation. However, endogenously produced uremic toxins (UTs) cannot always be filtered during dialysis. UTs are among the CKD-related factors that have been linked to maladaptive and pathophysiological remodeling of the heart. Importantly, 50% of the deaths in dialysis patients are cardiovascular related, with sudden cardiac death predominating. However, the mechanisms responsible remain poorly understood. The current study aimed to assess the vulnerability of action potential repolarization caused by exposure to pre-identified UTs at clinically relevant concentrations. We exposed human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and HEK293 chronically (48 h) to the UTs indoxyl sulfate, kynurenine, or kynurenic acid. We used optical and manual electrophysiological techniques to assess action potential duration (APD) in the hiPSC-CMs and recorded I Kr currents in stably transfected HEK293 cells (HEK-hERG). Molecular analysis of K V11.1, the ion channel responsible for I Kr, was performed to further understand the potential mechanism underlying the effects of the UTs. Chronic exposure to the UTs resulted in significant APD prolongation. Subsequent assessment of the repolarization current I Kr, often most sensitive and responsible for APD alterations, showed decreased current densities after chronic exposure to the UTs. This outcome was supported by lowered protein levels of K V11.1. Finally, treatment with an activator of the I Kr current, LUF7244, could reverse the APD prolongation, indicating the potential modulation of electrophysiological effects caused by these UTs. This study highlights the pro-arrhythmogenic potential of UTs and reveals a mode of action by which they affect cardiac repolarization.

KW - K 11.1

KW - cardiac repolarization

KW - cellular electrophysiology

KW - chronic kidney disease

KW - uremic toxins

UR - http://www.scopus.com/inward/record.url?scp=85151108914&partnerID=8YFLogxK

U2 - 10.3390/ijms24065373

DO - 10.3390/ijms24065373

M3 - Article

C2 - 36982449

SN - 1422-0067

VL - 24

JO - International Journal of Molecular Sciences

JF - International Journal of Molecular Sciences

IS - 6

M1 - 5373

ER -

Pro-Arrhythmic Potential of Accumulated Uremic Toxins Is Mediated via Vulnerability of Action Potential Repolarization

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