The microbial metabolite p-cresol compromises the vascular barrier and induces endothelial cytotoxicity and inflammation in a 3D human vessel-on-a-chip
Issued Date
2024-12-01
Resource Type
eISSN
20452322
Scopus ID
2-s2.0-85200849549
Journal Title
Scientific Reports
Volume
14
Issue
1
Rights Holder(s)
SCOPUS
Bibliographic Citation
Scientific Reports Vol.14 No.1 (2024)
Suggested Citation
Mankhong S., Den-Udom T., Tanawattanasuntorn T., Suriyun T., Muta K., Kitiyakara C., Ketsawatsomkron P. The microbial metabolite p-cresol compromises the vascular barrier and induces endothelial cytotoxicity and inflammation in a 3D human vessel-on-a-chip. Scientific Reports Vol.14 No.1 (2024). doi:10.1038/s41598-024-69124-w Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/100531
Title
The microbial metabolite p-cresol compromises the vascular barrier and induces endothelial cytotoxicity and inflammation in a 3D human vessel-on-a-chip
Author's Affiliation
Corresponding Author(s)
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Abstract
Increased protein-bound uremic toxins (PBUTs) in patients with chronic kidney disease (CKD) are associated with cardiovascular diseases (CVDs); however, whether retention of PBUTs causes CVD remains unclear. Previous studies assessing the impacts of PBUTs on the vasculature have relied on 2D cell cultures lacking in vivo microenvironments. Here, we investigated the impact of various PBUTs (p-cresol (PC), indoxyl sulfate (IS), and p-cresyl sulfate (PCS)) on microvascular function using an organ-on-a-chip (OOC). Human umbilical vein endothelial cells were used to develop 3D vessels. Chronic exposure to PC resulted in significant vascular leakage compared with controls, whereas IS or PCS treatment did not alter the permeability of 3D vessels. Increased permeability induced by PC was correlated with derangement of cell adherens junction complex, vascular endothelial (VE)-cadherin and filamentous (F)-actin. Additionally, PC decreased endothelial viability in a concentration-dependent manner with a lower IC50 in 3D vessels than in 2D cultures. IS slightly decreased cell viability, while PCS did not affect viability. PC induced inflammatory responses by increasing monocyte adhesion to endothelial surfaces of 3D vessels and IL-6 production. In conclusion, this study leveraged an OOC to determine the diverse effects of PBUTs, demonstrating that PC accumulation is detrimental to ECs during kidney insufficiency.