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Modeling Uremic Vasculopathy With Induced Pluripotent Stem Cell-Derived Endothelial Cells as a Drug Screening System
Jang,Hye Ryoun1; Cho,Hyung Joon2; Zhou,Yang3; Shao,Ning Yi4; Lee,Kyungho1; Le,Hoai Huong Thi5; Jeon,Junseok1; Lee,Jung Eun1; Huh,Wooseong1; Ong,Sang Ging6,7; Lee,Won Hee5; Kim,Yoon Goo1
2021-01-12
Source PublicationFrontiers in Cell and Developmental Biology
ISSN2296-634X
Volume8
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.

KeywordChronic Kidney Disease Endothelial Cells Induced Pluripotent Stem Cells Uremic Toxin Uremic Vasculopathy
DOI10.3389/fcell.2020.618796
URLView the original
Indexed BySCIE
Language英語English
WOS Research AreaCell Biology ; Developmental Biology
WOS SubjectCell Biology ; Developmental Biology
WOS IDWOS:000611506300001
Scopus ID2-s2.0-85099994038
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Cited Times [WOS]:0   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionUniversity of Macau
Corresponding AuthorLee,Won Hee; Kim,Yoon Goo
Affiliation1.Division of Nephrology,Department of Medicine,Samsung Medical Center,Stem Cell Regenerative Medicine Institute(SCRMI),Sungkyunkwan University School of Medicine,Seoul,South Korea
2.School for Engineering of Matter,Transport Energy,Arizona State University,Tempe,United States
3.Stanford Cardiovascular Institute,Stanford University School of Medicine,Stanford,United States
4.Health Sciences,University of Macau,Macao
5.Department of Basic Medical Sciences,University of Arizona College of Medicine,Phoenix,United States
6.Department of Pharmacology Regenerative Medicine,University of Illinois College of Medicine,Chicago,United States
7.Division of Cardiology,Department of Medicine,University of Illinois College of Medicine,Chicago,United States
Recommended Citation
GB/T 7714
Jang,Hye Ryoun,Cho,Hyung Joon,Zhou,Yang,et al. Modeling Uremic Vasculopathy With Induced Pluripotent Stem Cell-Derived Endothelial Cells as a Drug Screening System[J]. Frontiers in Cell and Developmental Biology,2021,8.
APA Jang,Hye Ryoun,Cho,Hyung Joon,Zhou,Yang,Shao,Ning Yi,Lee,Kyungho,Le,Hoai Huong Thi,Jeon,Junseok,Lee,Jung Eun,Huh,Wooseong,Ong,Sang Ging,Lee,Won Hee,&Kim,Yoon Goo.(2021).Modeling Uremic Vasculopathy With Induced Pluripotent Stem Cell-Derived Endothelial Cells as a Drug Screening System.Frontiers in Cell and Developmental Biology,8.
MLA Jang,Hye Ryoun,et al."Modeling Uremic Vasculopathy With Induced Pluripotent Stem Cell-Derived Endothelial Cells as a Drug Screening System".Frontiers in Cell and Developmental Biology 8(2021).
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