p-Cresyl sulfate promotes smooth muscle cell proliferation and endothelial dysfunction, leading to development of...

Vascular access failure is a major cause of morbidity in hemodialysis patients, primarily driven by smooth muscle cell (SMC) proliferation-related neointimal hyperplasia. The uremic toxin p-cresyl sulfate (p-CS) has been linked to poor vascular access outcomes, but its pathogenic mechanisms remain unclear. This study investigated whether p-CS promotes SMC proliferation and induces endothelial dysfunction, and contributes to neointimal hyperplasia.

Human aortic SMCs were treated with p-CS to assess proliferation and activation of ERK1/2 and p38 MAPK signaling. In human umbilical vein endothelial cells (HUVECs), oxidative stress and expression of inflammatory mediators (NF-κB, ICAM-1, MCP-1) were measured at mRNA and protein levels, along with eNOS and iNOS expression. A Transwell co-culture system was used to evaluate whether p-CS-induced endothelial alterations affect SMC proliferation. Neointimal formation after p-CS exposure was confirmed using an ex vivo mouse aorta model.

p-CS promoted SMC proliferation in a dose-dependent manner and activated ERK1/2 and p38 MAPK. In HUVECs, p-CS induced ROS generation and increased NF-κB, ICAM-1, and MCP-1 expression, while upregulating iNOS and suppressing eNOS. In co-culture, p-CS-stimulated HUVECs enhanced SMC proliferation; this effect was attenuated by NAC, probenecid, or neutralizing antibodies against MCP-1 and ICAM-1. In the ex vivo aorta model, p-CS induced neointimal hyperplasia accompanied by elevated α-SMA, ICAM-1, and MCP-1 expression.

These findings suggest that p-CS may promote SMC proliferation both directly and indirectly through endothelial dysfunction, ultimately contributing to neointimal hyperplasia. Further studies are needed to clarify the clinical implications of p-CS in vascular access dysfunction.