Department of Cardiology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
Department of Cardiology, Dushu Lake Hospital Affiliated to Soochow University, Suzhou, Jiangsu, China.
JCI Insight. 2022 Feb 8;7(3):e145475. doi: 10.1172/jci.insight.145475.
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.
在患有慢性肾脏病（CKD）的患者中，与心脏性猝死相关的室性心律失常的发生率很高。为了探索 CKD 相关室性心律失常的可能机制，建立了 CKD 大鼠模型，并进一步在体内和体外使用了硫酸吲哚酚（IS）。本项目采用了以下方法：膜片钳、心电图和一些分子生物学实验技术。发现 CKD 大鼠血清中的 IS 明显升高。有趣的是，CKD 大鼠和 IS 处理大鼠心脏中的快速瞬时外向钾电流相关（Ito,f 相关）蛋白（Kv4.2、Kv4.3 和 KChIP2）的表达水平降低。IS 呈剂量依赖性降低 Ito,f 密度，体外同时伴有 Kv4.2、Kv4.3 和 KChIP2 蛋白减少。IS 还延长了动作电位时程和 QT 间期，并可诱发 IS 阵发性室性心动过速。深入研究表明，ROS/p38MAPK、ROS-p44/42 MAPK 和 NF-κB 信号通路在 IS 引起的 Ito,f 密度和 Ito,f 相关蛋白减少中起关键作用。这些数据表明，IS 通过激活 ROS/MAPK 和 NF-κB 信号通路来减少 Ito,f 相关蛋白和 Ito,f 密度，随后延长动作电位时程和 QT 间期，这有助于增加 CKD 患者心律失常的易感性。
