Abstract Chronic kidney disease is linked to impaired cognitive function and increased neurovascular disease risk even after correction for classical risk factors. The mechanism(s) underlying these links are unclear but may involve interactions of uraemic toxins with the blood-brain barrier (BBB). Here, we studied how the major uraemic toxin p -cresol sulfate (pCS) could affect BBB integrity. Exposure of human hCMEC/D3 endothelial cells to pCS dose-dependently increased paracellular permeability and disrupted intercellular tight junctions, a permeabilising effect mirrored in mice. Whole brain RNAseq analysis identified pCS-mediated suppression of neuronal activity, transcription and mitochondrial respiration pathways. In vitro studies identified pCS binding to the epidermal growth factor receptor (EGFR), leading via annexin A1 and STAT3 signalling to mobilisation of matrix metalloproteinase (MMP)-2/9. Confirming this pathway in vivo , the BBB damaging effects of pCS were prevented by pre-treatment with the EGFR antagonist erlotinib or the MMP2/9 inhibitor SB-3CT. Finally, hCMEC/D3 cells exposed to haemodialysis patient serum, but not to that of healthy donors, showed an erlotinib-sensitive increase in paracellular permeability that closely correlated in size to the total serum pCS content. Overall, we define a pathway linking the uraemic toxin pCS with BBB damage suggesting that targeting the EGFR may be useful in mitigating against cerebrovascular damage in chronic kidney disease. Translational Statement Patients with chronic kidney disease (CKD) have increased risk of cognitive impairment and stroke, pathologies associated cerebromicrovascular disease, but it is not clear why. Here, we show that the uraemic toxin p-cresol sulfate impairs BBB function in vitro and in vivo through EGFR-dependent MMP mobilisation. Importantly, serum from haemodialysis patients can also impair permeability of an in vitro BBB model, an effect prevented by EGFR inhibition, and proportional in magnitude to serum pCS content. Our data suggest that existing EGFR inhibitory drugs might have utility in preventing cerebral small vessel disease in CKD patients.

Cerebrovascular damage caused by the gut microbe-derived uraemic toxin<i>p</i>-cresol sulfate is prevented by blockade of the epidermal growth factor receptor

Cerebrovascular damage caused by the gut microbe-derived uraemic toxinp-cresol sulfate is prevented by blockade of the epidermal growth factor receptor