Figure 3.

Mechanisms underlying indoxyl sulfate-induced endothelial dysfunction. The uremic toxin indoxyl sulfate (IS), which highly accumulates in CKD patients, leads to endothelial dysfunction by enhancing oxidative stress, endothelial inflammation, recruitment and adhesion of inflammatory cells, cell death as well as by reducing endothelial proliferation. In addition, it reduces endothelial nitric oxide production, contributing to enhanced vascular stiffness. As underlying mechanisms, IS induces the production of reactive oxygen species (ROS) and binds to the Aryl Hydrocarbon Receptor (AhR), thereby enhancing intracellular signaling through MAP Kinases (ERK, p38, JNK) and NF-κB (p65), triggering pro-inflammatory and apoptotic responses in endothelial cells (A). In addition, IS-AhR pro-inflammatory activation of monocytes contributes to endothelial dysfunction (B). With the focus on the cell signaling pathways, the figure does not take into account a differentiation between basal and apical side of the cell. AhR = Aryl Hydrocarbon Receptor, AP-1 = activator protein-1; eNOS = endothelial nitric oxide synthase; MAPK = mitogen activated protein kinase; NF-κB = nuclear factor kappa B; NO = nitric oxide; p-eNOS = phosphorylated, active eNOS; ROS = reactive oxygen species; TNF = tumor necrosis factor.