Indoxyl sulfate reduces Ito,f by activating ROS/MAPK and NF-κB signaling pathways.
Indoxyl sulfate reduces Ito,f by activating ROS/MAPK and NF-κB signaling pathways.
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硫酸吲哚酚通过激活 ROS/MAPK 和 NF-κB 信号通路来减少 Ito,f
DOI：
10.1172/jci.insight.145475
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发表时间：
2022-02-08
期刊：
影响因子：
8
通讯作者：
Zhou Y
中科院分区：
文献类型：
--
作者：
Yang J;Li H;Zhang C;Zhou Y
慢性肾病（CKD）患者中与心脏性猝死相关的室性心律失常患病率很高。为探讨CKD相关性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硫酸吲哚酚（IS）。本课题主要采用了膜片钳、心电图、分子生物学等实验技术。CKD大鼠血清IS明显升高。有趣的是，CKD大鼠和IS治疗大鼠心脏中快速瞬时外向钾电流相关（Ito，f相关）蛋白（Kv4.2，Kv4.3和KChIP 2）的表达水平降低。IS剂量依赖性地降低Ito，f密度，伴随着Kv4.2，Kv4.3和KChIP 2蛋白在体外的减少。IS还延长动作电位时程和QT间期，并可诱发阵发性室性心动过速。深入研究表明，ROS/p38 MAPK、ROS-p44/42 MAPK和NF-κB信号通路在IS引起的Ito，f密度降低和Ito，f相关蛋白降低中起关键作用。提示缺血再灌注可通过激活ROS/MAPK和NF-κB信号通路，降低Ito，f相关蛋白和Ito，f密度，延长动作电位时程和QT间期，增加CKD心律失常的易感性。
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.
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影响因子：
20.1
作者：
BEUCKELMANN, DJ;NABAUER, M;ERDMANN, E
通讯作者：
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影响因子：
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DOI：
10.2215/cjn.04730514
发表时间：
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影响因子：
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作者：
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作者：
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