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. 2020 Jun 20;12(6):412. doi: 10.3390/toxins12060412

Figure 3.

Figure 3

Uremic toxins activate the aryl hydrocarbon receptor (AhR), nuclear factor kappa B (NF-κB), and mitogen-activated protein kinase (MAPK) pathways in endothelial cells. Toxins such as indoxyl sulfate (IS) and indole-3 acetic acid (IAA) activate AhR, which is translocated to the nucleus, forms a dimer with aryl hydrocarbon receptor nuclear translocator (ARNT), and induces the expression of CYP1A1, CYP1B1, and AhRR (genomic pathway). Activated AhR can stimulate other pathways (non-genomic pathway), including the activation of AP-1 that induces E-selectin expression. Uremic toxins also cause the activation of the MAPK pathway, such as p38MAPK and ERK1/2, by phosphorylation. MAPK and AhR can induce the NF-κB pathway. In uremic conditions, IκB is degraded and p50/p65 are translocated to the nucleus, inducing monocyte chemoattractant protein-1 (MCP-1), intercellular adhesion molecule-1 (ICAM-1), cyclooxygenase-2 (COX-2), and tissue factor (TF) expression. The activation of these pathways by uremic toxins can lead to endothelial dysfunction.