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

Jing Yang1,2, Hongxia Li1, Chi Zhang1

  • 1Department of Cardiology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.

JCI Insight
|February 8, 2022
PubMed

Insights

Indoxyl sulfate (IS), elevated in chronic kidney disease (CKD), reduces key heart proteins (Kv4.2, Kv4.3, KChIP2) and potassium currents, increasing arrhythmia risk.

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.
Keywords:
ArrhythmiasCardiologyIon channelsMolecular biology

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