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Modeling Uremic Vasculopathy With Induced Pluripotent Stem Cell-Derived Endothelial Cells as a Drug Screening System.
- Source :
-
Frontiers in cell and developmental biology [Front Cell Dev Biol] 2021 Jan 12; Vol. 8, pp. 618796. Date of Electronic Publication: 2021 Jan 12 (Print Publication: 2020). - Publication Year :
- 2021
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Abstract
- Background: Cardiovascular complications are the leading cause of mortality in patients with chronic kidney disease (CKD). Uremic vasculopathy plays a crucial role in facilitating the progression of cardiovascular complications in advanced CKD. However, the improvement of conventional research methods could provide further insights into CKD. Objectives: In this study, we aimed to develop a novel model of uremic vasculopathy as a potential drug screening system. Methods and Results: The effects of uremic serum and different combinations of uremic toxins on induced pluripotent stem cell (iPSC)-derived endothelial cells (ECs) of a normal control and a CKD patient were investigated using several functional assays. We found that a mixture of uremic toxins composed of high urea, creatinine, uric acid, and indoxyl sulfate exerted deleterious effects on normal control iPSC-ECs that were comparable to uremic serum by increasing reactive oxygen species and apoptosis, as well as suppression of tube formation. Additional characterization revealed a potential involvement of dysregulated TGF-β signaling as treatment with either losartan or TGF-β inhibitors led to the attenuation of adverse effects induced by uremic toxins. Importantly, impaired wound healing potential seen in CKD patient-specific iPSC-ECs was rescued by treatment with losartan and TGF-β inhibitors. Conclusion: Our study demonstrated that simplified uremic toxin mixtures can simulate the uremic micromilieu reproducibly and CKD patient-specific iPSC-ECs can potentially recapitulate susceptibility to uremic vasculopathy. This novel model of uremic vasculopathy may provide a new research tool as a drug screening system.<br />Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.<br /> (Copyright © 2021 Jang, Cho, Zhou, Shao, Lee, Le, Jeon, Lee, Huh, Ong, Lee and Kim.)
Details
- Language :
- English
- ISSN :
- 2296-634X
- Volume :
- 8
- Database :
- MEDLINE
- Journal :
- Frontiers in cell and developmental biology
- Publication Type :
- Academic Journal
- Accession number :
- 33511129
- Full Text :
- https://doi.org/10.3389/fcell.2020.618796