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Uremic retention solute indoxyl sulfate level is associated with prolonged QTc interval in early CKD patients.

Tang WH, Wang CP, Chung FM, Huang LL, Yu TH, Hung WC, Lu LF, Chen PY, Luo CH, Lee KT, Lee YJ, Lai WT - PLoS ONE (2015)

Bottom Line: Furthermore, serum IS level was independently associated with prolonged QTc interval.In vitro, the delay rectifier potassium current (IK) was found to be significantly decreased after the treatment of IS in a dose-dependent manner.In conclusion, serum IS level is independently associated with the prolonged QTc interval in early CKD patients.

View Article: PubMed Central - PubMed

Affiliation: Graduate Institute of Medicine, Collage of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Division of Cardiology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.

ABSTRACT
Total mortality and sudden cardiac death is highly prevalent in patients with chronic kidney disease (CKD). In CKD patients, the protein-bound uremic retention solute indoxyl sulfate (IS) is independently associated with cardiovascular disease. However, the underlying mechanisms of this association have yet to be elucidated. The relationship between IS and cardiac electrocardiographic parameters was investigated in a prospective observational study among early CKD patients. IS arrhythmogenic effect was evaluated by in vitro cardiomyocyte electrophysiological study and mathematical computer simulation. In a cohort of 100 early CKD patients, patients with corrected QT (QTc) prolongation had higher IS levels. Furthermore, serum IS level was independently associated with prolonged QTc interval. In vitro, the delay rectifier potassium current (IK) was found to be significantly decreased after the treatment of IS in a dose-dependent manner. The modulation of IS to the IK was through the regulation of the major potassium ion channel protein Kv 2.1 phosphorylation. In a computer simulation, the decrease of IK by IS could prolong the action potential duration (APD) and induce early afterdepolarization, which is known to be a trigger mechanism of lethal ventricular arrhythmias. In conclusion, serum IS level is independently associated with the prolonged QTc interval in early CKD patients. IS down-regulated IK channel protein phosphorylation and the IK current activity that in turn increased the cardiomyocyte APD and QTc interval in vitro and in the computer ORd model. These findings suggest that IS may play a role in the development of arrhythmogenesis in CKD patients.

No MeSH data available.


Related in: MedlinePlus

The effect of IS on H9c2 cardiomyocyte IK and potassium channel protein Kv2.1 expression.(A) The representative current traces for delayed rectifier potassium outward currents (Ik) in H9c2 cells with different indoxyl sulfate (IS) concentration treatment. Ik were elicited by 300 ms depolarizing step pulses from -70 to 50 mV at a holding potential of -60 mV. (B) The average relationships between Ik (pA/pF) and membrane potential in the control, 0.1μM IS, 1 μM IS and 300μM IS groups (n = 6 for each groups) comparing the IS treated group with the control group, Ik was significantly decreased at membrane potentials from 0 mV to 50 mV in a dose-dependent manner. (C and D) The expression of Kv2.1 and phosphorylated Kv2.1 by Western blot in the H9c2 cells treated with different concentration of IS (0.1μM, 1 μM and 300μM). The expressions of Kv2.1 were not significantly different among the control and IS-treated groups (C). However, the phosphorylated Kv2.1 was significantly decreased in the 1 μM IS-and 300 μM-IS treated groups (D). (n = 6 for each groups) *: p<0.05 as compared with the control group.
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pone.0119545.g001: The effect of IS on H9c2 cardiomyocyte IK and potassium channel protein Kv2.1 expression.(A) The representative current traces for delayed rectifier potassium outward currents (Ik) in H9c2 cells with different indoxyl sulfate (IS) concentration treatment. Ik were elicited by 300 ms depolarizing step pulses from -70 to 50 mV at a holding potential of -60 mV. (B) The average relationships between Ik (pA/pF) and membrane potential in the control, 0.1μM IS, 1 μM IS and 300μM IS groups (n = 6 for each groups) comparing the IS treated group with the control group, Ik was significantly decreased at membrane potentials from 0 mV to 50 mV in a dose-dependent manner. (C and D) The expression of Kv2.1 and phosphorylated Kv2.1 by Western blot in the H9c2 cells treated with different concentration of IS (0.1μM, 1 μM and 300μM). The expressions of Kv2.1 were not significantly different among the control and IS-treated groups (C). However, the phosphorylated Kv2.1 was significantly decreased in the 1 μM IS-and 300 μM-IS treated groups (D). (n = 6 for each groups) *: p<0.05 as compared with the control group.

Mentions: The results of the patch-clamp cell electrophysiological study revealed that the IK was significantly decreased after treatment with IS for 48 hours (Fig 1A). The average relationships between IK and membrane potential calculated from the measured peak current amplitudes showed that IK was significantly decreased at the membrane potentials from 0 mV to 50 mV in a dose-dependent manner (Fig 1B).


Uremic retention solute indoxyl sulfate level is associated with prolonged QTc interval in early CKD patients.

Tang WH, Wang CP, Chung FM, Huang LL, Yu TH, Hung WC, Lu LF, Chen PY, Luo CH, Lee KT, Lee YJ, Lai WT - PLoS ONE (2015)

The effect of IS on H9c2 cardiomyocyte IK and potassium channel protein Kv2.1 expression.(A) The representative current traces for delayed rectifier potassium outward currents (Ik) in H9c2 cells with different indoxyl sulfate (IS) concentration treatment. Ik were elicited by 300 ms depolarizing step pulses from -70 to 50 mV at a holding potential of -60 mV. (B) The average relationships between Ik (pA/pF) and membrane potential in the control, 0.1μM IS, 1 μM IS and 300μM IS groups (n = 6 for each groups) comparing the IS treated group with the control group, Ik was significantly decreased at membrane potentials from 0 mV to 50 mV in a dose-dependent manner. (C and D) The expression of Kv2.1 and phosphorylated Kv2.1 by Western blot in the H9c2 cells treated with different concentration of IS (0.1μM, 1 μM and 300μM). The expressions of Kv2.1 were not significantly different among the control and IS-treated groups (C). However, the phosphorylated Kv2.1 was significantly decreased in the 1 μM IS-and 300 μM-IS treated groups (D). (n = 6 for each groups) *: p<0.05 as compared with the control group.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4403985&req=5

pone.0119545.g001: The effect of IS on H9c2 cardiomyocyte IK and potassium channel protein Kv2.1 expression.(A) The representative current traces for delayed rectifier potassium outward currents (Ik) in H9c2 cells with different indoxyl sulfate (IS) concentration treatment. Ik were elicited by 300 ms depolarizing step pulses from -70 to 50 mV at a holding potential of -60 mV. (B) The average relationships between Ik (pA/pF) and membrane potential in the control, 0.1μM IS, 1 μM IS and 300μM IS groups (n = 6 for each groups) comparing the IS treated group with the control group, Ik was significantly decreased at membrane potentials from 0 mV to 50 mV in a dose-dependent manner. (C and D) The expression of Kv2.1 and phosphorylated Kv2.1 by Western blot in the H9c2 cells treated with different concentration of IS (0.1μM, 1 μM and 300μM). The expressions of Kv2.1 were not significantly different among the control and IS-treated groups (C). However, the phosphorylated Kv2.1 was significantly decreased in the 1 μM IS-and 300 μM-IS treated groups (D). (n = 6 for each groups) *: p<0.05 as compared with the control group.
Mentions: The results of the patch-clamp cell electrophysiological study revealed that the IK was significantly decreased after treatment with IS for 48 hours (Fig 1A). The average relationships between IK and membrane potential calculated from the measured peak current amplitudes showed that IK was significantly decreased at the membrane potentials from 0 mV to 50 mV in a dose-dependent manner (Fig 1B).

Bottom Line: Furthermore, serum IS level was independently associated with prolonged QTc interval.In vitro, the delay rectifier potassium current (IK) was found to be significantly decreased after the treatment of IS in a dose-dependent manner.In conclusion, serum IS level is independently associated with the prolonged QTc interval in early CKD patients.

View Article: PubMed Central - PubMed

Affiliation: Graduate Institute of Medicine, Collage of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Division of Cardiology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.

ABSTRACT
Total mortality and sudden cardiac death is highly prevalent in patients with chronic kidney disease (CKD). In CKD patients, the protein-bound uremic retention solute indoxyl sulfate (IS) is independently associated with cardiovascular disease. However, the underlying mechanisms of this association have yet to be elucidated. The relationship between IS and cardiac electrocardiographic parameters was investigated in a prospective observational study among early CKD patients. IS arrhythmogenic effect was evaluated by in vitro cardiomyocyte electrophysiological study and mathematical computer simulation. In a cohort of 100 early CKD patients, patients with corrected QT (QTc) prolongation had higher IS levels. Furthermore, serum IS level was independently associated with prolonged QTc interval. In vitro, the delay rectifier potassium current (IK) was found to be significantly decreased after the treatment of IS in a dose-dependent manner. The modulation of IS to the IK was through the regulation of the major potassium ion channel protein Kv 2.1 phosphorylation. In a computer simulation, the decrease of IK by IS could prolong the action potential duration (APD) and induce early afterdepolarization, which is known to be a trigger mechanism of lethal ventricular arrhythmias. In conclusion, serum IS level is independently associated with the prolonged QTc interval in early CKD patients. IS down-regulated IK channel protein phosphorylation and the IK current activity that in turn increased the cardiomyocyte APD and QTc interval in vitro and in the computer ORd model. These findings suggest that IS may play a role in the development of arrhythmogenesis in CKD patients.

No MeSH data available.


Related in: MedlinePlus