P-cresol induces disruption of cardiomyocyte adherens junctions.

Higher serum levels of p-cresol in chronic kidney disease populations have been associated with increased cardiovascular mortality. However, studies on how p-cresol affects intercellular junctions between cardiomyocytes were limited. This study investigated the effect of p-cresol on adherens junction (AJ) of neonatal cultured cardiomyocytes and its underlying mechanism. A loss of N-cadherin and p120-catenin (p120ctn) immunostaining from cell-cell contact sites was noted by p-cresol treatment. In addition, p-cresol disrupted AJs by inducing formation of intercellular gaps. Our previous study has revealed that p-cresol increased intracellular calcium levels and activated protein kinase Cα (PKCα) by phosphorylation. The PKCα activation was involved in the p-cresol-mediated AJ disassembly, since pharmacological inhibition of PKCα abolished the above-mentioned p-cresol effect. This PKCα activation also led to the serine dephosphorylation of p120ctn and caused the dissociation of p120ctn from N-cadherin. This hypothesis was further confirmed in H9c2 cells by siRNA approach. SiRNA knockdown of PKCα prevented p-cresol-induced serine dephosphorylation of p120ctn and splitting of AJ. In conclusion, p-cresol caused PKCα-dependent AJ disassembly of cardiomyocytes, which might be related to asychronized contraction.