Uremic toxin indoxyl sulfate suppresses myocardial Cx43 assembly and expression via JNK activation

Area of Science:

• Cardiovascular Science
• Nephrology
• Cell Biology

Background:

• Heart rhythm disturbances are a major cause of cardiovascular mortality in chronic kidney disease (CKD).
• Uremic toxins, particularly indoxyl sulfate (IS), contribute to cardiovascular complications in CKD.
• Connexin 43 (Cx43) gap junctions are crucial for cardiomyocyte synchronization and may be affected by uremic toxins.

Purpose of the Study:

• To investigate the effect of indoxyl sulfate (IS) on cardiomyocyte function and Connexin 43 (Cx43) expression.
• To elucidate the role of the JNK signaling pathway in IS-induced cardiac alterations.
• To examine Cx43 expression in a preclinical model of CKD.

Main Methods:

• Primary cultures of rat neonatal cardiomyocytes and H9c2 cells were treated with IS.
• Measurements included spontaneous contraction, gap junction intercellular communication (GJIC), Cx43 protein and mRNA levels, and JNK phosphorylation.
• A JNK inhibitor (SP600125) was used to assess the pathway's involvement.
• Cx43 levels were examined in cardiac muscle from nephrectomy-induced CKD mice.

Main Results:

• IS treatment reduced cardiomyocyte spontaneous contraction and disrupted GJIC.
• IS caused time- and dose-dependent Cx43 redistribution, downregulation of Cx43 protein and mRNA.
• IS exposure led to increased JNK1/JNK2 phosphorylation.
• JNK inhibition reversed IS-induced effects on GJIC and Cx43 expression.
• Altered Cx43 levels were observed in the cardiac muscle of CKD mice.

Conclusions:

• Indoxyl sulfate impairs cardiomyocyte function and gap junction communication.
• JNK pathway activation is a key mechanism underlying IS-induced Cx43 remodeling in the heart.
• These findings highlight a potential therapeutic target for cardiovascular complications in CKD.