Maintaining Cerebral-Endothelial Integrity and Permeability Guard Against Uremic Toxins Induced Cognitive Impairment

Abstract

Chronic kidney disease (CKD) is with a characterization of progressing loss of renal function; commonly, CKD progression leads to multiple comorbidities, including neurological dysfunction and immune disorders. Our previous study reported that accumulation of uremic toxins, including creatinine, blood urea nitrogen (BUN), indoxyl sulfate (IS), and p-cresol sulfate (PCS), could not only induce neuronal inflammation, but also NLRP3-inflammasome-correlated astrocytic inflammation; both neuronal and astrocytic inflammation significantly contribute to CKD-triggered cognitive impairment. Our study also demonstrated that AST-120, an IS and PCS absorbent, effectively reduced serum and hippocampal IS and PCS levels and hippocampal inflammation as well as reversed the cognitive function in CKD mice. The current study aims to understand how IS and PCS passing through endothelial cells and affecting endothelial physiology, consequently, compromises cerebral-endothelial and blood-brain-barrier (BBB) function. The results of Evans blue assay and Western blotting of this study have shown that 5/6 nephrectomy CKD mice occurred leakage of BBB and IS treatment could trigger NLRP3 inflammasome-mediated endothelial inflammation respectively. Moreover, Western blotting assay also indicated expression of endothelial tight-junction proteins was altered by IS and immunocytochemistry images showed that the aryl hydrocarbon receptor (AhR) was activated and relocated to nuclei of endothelial cells. Furthermore, images of immunocytochemistry revealed that the organic anion transporter (OAT) inhibiters, chloroquine and hydroxychloroquine, prohibit IS-induced AhR relocation to endothelial nuclei. Therefore, we postulated that IS and PCS pass through endothelial membrane via certain types of OATs/OATPs and activate AhRs relocating to nuclei, subsequently, induce endothelial inflammation, alter expression of tight-junction proteins, and dysregulate permeability of BBB. The goal of our study is to decipher mechanisms of aromatic uremic toxins, specially IS and PCS, induced cognitive impairment and find out possible treatments via blocking IS/PCS endothelial transcytosis, suppressing endothelial AhR activity, preventing endothelial inflammation, and maintaining endothelial permeability. The study is funded by National Science and Technology Committee of Taiwan, grant number 111-2320-B-128A-004 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.