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 8

IS downregulated Ito,f density and prolonged APD by activating p38 MAPK, p44/42 MAPK, and NF-κB signaling pathways.

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IS downregulated Ito,f density and prolonged APD by activating p38 MAPK,...
(A and D) Representative Ito,f traces (A) and average Ito,f densities (peak minus steady state) versus membrane potentials (D) in control, SB, IS, and IS plus SB groups (n = 5 per group). &P < 0.05, &&P < 0.01 SB versus Control. #P < 0.05, ##P < 0.05 IS plus SB versus IS. **P < 0.01 IS versus control. (B and E) Representative Ito,f traces (B) and average Ito,f densities (peak minus steady state) versus membrane potentials (E) in control, U0126, IS, and IS plus U0126 groups (n = 5 per group). &P < 0.05 U0126 versus Control. #P < 0.05, ##P < 0.05 IS plus U0126 versus IS. **P < 0.01 IS versus control. (C and F) Representative Ito,f traces (C) and average Ito,f densities (peak minus steady state) versus membrane potentials (F) in control, BAY, IS, and IS plus BAY groups (n = 5 per group). &P < 0.05, &&P < 0.01 BAY versus Control. #P < 0.05, ##P < 0.05 IS plus BAY versus IS. **P < 0.01 IS versus control. (G–I) Representative AP traces from different groups treated with or without SB (G), U0126 (H), or BAY (I). (J–L) Average values of APD50 and APD90 in different groups treated with or without SB (J), U0126 (K), or BAY (L) (n = 5 per group). *P < 0.05, **P < 0.01. NRVMs in IS, IS plus SB, IS plus U0126, and IS plus BAY groups were treated with 10 μM IS. SB, SB203580; U0126, U0126-EtOH; BAY, BAY11-7082. Data are presented as mean ± SEM. Statistical analysis was performed using 1-way ANOVA, followed by Bonferroni post hoc test.