P-cresol induces disruption of cardiomyocyte adherens junctions

Area of Science:

• Cardiovascular Biology
• Cell Biology
• Toxicology

Background:

• Elevated serum p-cresol is linked to cardiovascular mortality in chronic kidney disease (CKD).
• The impact of p-cresol on cardiomyocyte intercellular junctions remains poorly understood.
• Adherens junctions (AJs) are crucial for cardiomyocyte integrity and function.

Purpose of the Study:

• To investigate the effect of p-cresol on adherens junctions (AJs) in neonatal cardiomyocytes.
• To elucidate the underlying molecular mechanisms of p-cresol-induced AJ disruption.
• To explore the role of protein kinase Cα (PKCα) in this process.

Main Methods:

• Neonatal rat cardiomyocytes and H9c2 cells were treated with p-cresol.
• Immunostaining was used to assess N-cadherin and p120-catenin (p120ctn) localization.
• Pharmacological inhibition and siRNA knockdown of PKCα were employed.
• Western blotting was used to analyze protein phosphorylation and interactions.

Main Results:

• P-cresol treatment led to loss of N-cadherin and p120ctn from cell-cell contacts and induced intercellular gaps.
• P-cresol increased intracellular calcium and activated PKCα.
• PKCα activation mediated p-cresol-induced AJ disassembly by causing serine dephosphorylation of p120ctn and its dissociation from N-cadherin.
• PKCα inhibition or knockdown prevented these effects.

Conclusions:

• P-cresol induces adherens junction disassembly in cardiomyocytes through a PKCα-dependent pathway.
• This disruption may contribute to the increased cardiovascular mortality observed in CKD patients.
• Targeting PKCα could be a potential therapeutic strategy for mitigating p-cresol toxicity.