Uremic toxins activate CREB/ATF1 in endothelial cells related to chronic kidney disease.

Uremic toxins, such as p-cresyl sulfate (PCS) and indoxyl sulfate (IS), contribute to endothelial dysfunction in chronic kidney disease (CKD). This process is mediated by several cellular pathways, but it is unclear whether cAMP-responsive element-binding protein (CREB) and activating transcription factor 1 (ATF1) participate in endothelial dysfunction in uremic conditions despite playing roles in inflammatory modulation. This study aimed to evaluate the expression, activation, and transcriptional activity of CREB/ATF1 in endothelial cells exposed to PCS, IS, and uremic serum (US). In vitro, ATF1 protein levels were increased by PCS and IS, whereas CREB levels were enhanced only by IS. Activation through CREB-Ser133 and ATF1-Ser63 phosphorylation was induced by PCS, IS, and US. We evaluated the CREB/ATF1 transcriptional activity by analyzing the expression of their target genes, including ICAM1, PTGS2, NOX1, and SLC22A6, which are related to endothelial dysfunction through their roles in vascular inflammation, oxidative stress, and cellular uptake of PCS and IS. The expression of ICAM1, PTGS2 and NOX1 genes was increased by PCS, IS, and US, whereas that of SLC22A6 was induced only by IS. KG-501, a CREB inhibitor, restored the inductive effects of PCS on ICAM1, PTGS2, and NOX1 expression; IS on ICAM1, PTGS2 and SLC22A6 expression; and US on NOX1 expression. The presence of CREB and ATF1 was observed in healthy arteries and in arteries of patients with CKD, which were structurally damaged. These findings suggest that CREB/ATF1 is activated by uremic toxins and may play a relevant role in endothelial dysfunction in CKD.