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

Area of Science:

• Cardiology
• Nephrology
• Molecular Biology

Background:

• Patients with chronic kidney disease (CKD) exhibit a high incidence of ventricular arrhythmias and sudden cardiac death.
• The precise mechanisms underlying CKD-related ventricular arrhythmias require further elucidation.

Purpose of the Study:

• To investigate the role of indoxyl sulfate (IS) in the development of ventricular arrhythmias in CKD.
• To explore the molecular mechanisms by which IS affects cardiac ion channels and electrical activity.

Main Methods:

• Establishment of a CKD rat model.
• In vivo and in vitro experiments using indoxyl sulfate (IS).
• Techniques included patch clamp, electrocardiography, and molecular biology assays.

Main Results:

• Indoxyl sulfate (IS) levels were significantly elevated in CKD rats.
• IS reduced the expression of fast transient outward potassium current (Ito,f)-related proteins (Kv4.2, Kv4.3, KChIP2) in cardiac tissue.
• IS dose-dependently decreased Ito,f density, prolonged action potential duration and QT interval, and induced ventricular tachycardia.
• ROS/MAPK and NF-κB signaling pathways were identified as key mediators in IS-induced reduction of Ito,f and related proteins.

Conclusions:

• Indoxyl sulfate (IS) contributes to ventricular arrhythmias in CKD by reducing Ito,f-related proteins and Ito,f density.
• Activation of ROS/MAPK and NF-κB signaling pathways by IS plays a critical role in arrhythmogenesis.
• These findings highlight IS as a potential therapeutic target for preventing cardiac arrhythmias in CKD patients.