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

Hubrecht Institute

Onderzoeksoutput: Bijdrage aan wetenschappelijk tijdschrift/periodieke uitgave › Artikel › Wetenschappelijk › peer review

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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 IKr currents in stably transfected HEK293 cells (HEK-hERG). Molecular analysis of KV11.1, the ion channel responsible for IKr, 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 IKr, 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 KV11.1. Finally, treatment with an activator of the IKr 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.

Originele taal-2	Engels
Tijdschrift	International Journal of Molecular Sciences
Volume	24
Nummer van het tijdschrift	6
DOI's	https://doi.org/10.3390/ijms24065373
Status	Gepubliceerd - 11 mrt. 2023

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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). https://doi.org/10.3390/ijms24065373

@article{a9bcfb7eef8943f68fcb06892f46abe4,

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 IKr currents in stably transfected HEK293 cells (HEK-hERG). Molecular analysis of KV11.1, the ion channel responsible for IKr, 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 IKr, 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 KV11.1. Finally, treatment with an activator of the IKr 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 = "Humans, Uremic Toxins, HEK293 Cells, Action Potentials, Induced Pluripotent Stem Cells/metabolism, Renal Dialysis, Myocytes, Cardiac, Renal Insufficiency, Chronic/metabolism",

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}",

year = "2023",

month = mar,

day = "11",

doi = "10.3390/ijms24065373",

language = "English",

volume = "24",

journal = "International Journal of Molecular Sciences",

issn = "1661-6596",

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

number = "6",

}

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, nr. 6. https://doi.org/10.3390/ijms24065373

Pro-Arrhythmic Potential of Accumulated Uremic Toxins Is Mediated via Vulnerability of Action Potential Repolarization. / van Ham, Willem B; Cornelissen, Carlijn M; Polyakova, Elizaveta et al.
In: International Journal of Molecular Sciences, Vol. 24, Nr. 6, 11.03.2023.

Onderzoeksoutput: Bijdrage aan wetenschappelijk tijdschrift/periodieke uitgave › Artikel › Wetenschappelijk › peer review

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 IKr currents in stably transfected HEK293 cells (HEK-hERG). Molecular analysis of KV11.1, the ion channel responsible for IKr, 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 IKr, 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 KV11.1. Finally, treatment with an activator of the IKr 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 IKr currents in stably transfected HEK293 cells (HEK-hERG). Molecular analysis of KV11.1, the ion channel responsible for IKr, 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 IKr, 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 KV11.1. Finally, treatment with an activator of the IKr 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 - Humans

KW - Uremic Toxins

KW - HEK293 Cells

KW - Action Potentials

KW - Induced Pluripotent Stem Cells/metabolism

KW - Renal Dialysis

KW - Myocytes, Cardiac

KW - Renal Insufficiency, Chronic/metabolism

U2 - 10.3390/ijms24065373

DO - 10.3390/ijms24065373

M3 - Article

C2 - 36982449

SN - 1661-6596

VL - 24

JO - International Journal of Molecular Sciences

JF - International Journal of Molecular Sciences

IS - 6

ER -

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

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