Indoxyl sulfate reduces Ito,f by activating ROS/MAPK and NF-κB signaling pathways
Jing Yang, Hongxia Li, Chi Zhang, Yafeng Zhou
Jing Yang, Hongxia Li, Chi Zhang, Yafeng Zhou
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Research Article Cardiology

Indoxyl sulfate reduces Ito,f by activating ROS/MAPK and NF-κB signaling pathways

Abstract

There is a high prevalence of ventricular arrhythmias related to sudden cardiac death in patients with chronic kidney disease (CKD). To explored the possible mechanism of CKD-related ventricular arrhythmias, a CKD rat model was created, and indoxyl sulfate (IS) was further used in vivo and in vitro. This project used the following methods: patch clamp, electrocardiogram, and some molecular biology experimental techniques. IS was found to be significantly elevated in the serum of CKD rats. Interestingly, the expression levels of the fast transient outward potassium current–related (Ito,f-related) proteins (Kv4.2, Kv4.3, and KChIP2) in the heart of CKD rats and rats treated with IS decreased. IS dose-dependently reduced Ito,f density, accompanied by the decreases in Kv4.2, Kv4.3, and KChIP2 proteins in vitro. IS also prolonged the action potential duration and QT interval, and paroxysmal ventricular tachycardia could be induced by IS. In-depth studies have shown that ROS/p38MAPK, ROS–p44/42 MAPK, and NF-κB signaling pathways play key roles in the reduction of Ito,f density and Ito,f-related proteins caused by IS. These data suggest that IS reduces Ito,f-related proteins and Ito,f density by activating ROS/MAPK and NF-κB signaling pathways, and the action potential duration and QT interval are subsequently prolonged, which contributes to increasing the susceptibility to arrhythmia in CKD.

Authors

Jing Yang, Hongxia Li, Chi Zhang, Yafeng Zhou

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Figure 5

IS reduced Ito,f densities by generating ROS.

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IS reduced Ito,f densities by generating ROS. (A and B) Representative I...
(A and B) Representative Ito,f traces (A) and average Ito,f densities (peak minus steady state) versus membrane potentials (B) in control, NAC, IS, and IS plus NAC groups (n = 5 per group). &P < 0.05, &&P < 0.01 NAC versus Control. #P < 0.05 IS plus NAC versus IS. **P < 0.01 IS versus control. (C and D) Average values of half-maximal voltage of activation (V0.5, act) (C) and constants(k) of activation (D) in control, NAC, IS, and IS plus NAC groups (n = 5 per group). *P < 0.05, **P < 0.01. (E) Voltage-dependent activation curves of Ito,f in 4 groups (n = 5 per group). (F) Average time constants (τ) of decay of Ito,f at +60 mV in 4 groups (n = 5 per group). **P < 0.01. (G) Average values of APD50 and APD90 in control, NAC, IS, and IS plus NAC groups (n = 5 per group). **P < 0.01. (H) Representative AP traces from 4 groups. NRVMs in IS and IS plus NAC groups were treated with 10 μM IS. NAC, N-acetylcysteine. Data are presented as mean ± SEM. Statistical analysis was performed using 1-way ANOVA, followed by Bonferroni post hoc test.