Modeling Uremic Vasculopathy With Induced Pluripotent Stem Cell-Derived Endothelial Cells as a Drug Screening System

Hye Ryoun Jang, Hyung Joon Cho, Yang Zhou, Ning Yi Shao, Kyungho Lee, Hoai Huong Thi Le, Junseok Jeon, Jung Eun Lee, Wooseong Huh, Sang Ging Ong, Won Hee Lee, Yoon Goo Kim

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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.

Original languageEnglish (US)
Article number618796
JournalFrontiers in Cell and Developmental Biology
Volume8
DOIs
StatePublished - Jan 12 2021
Externally publishedYes

Keywords

  • chronic kidney disease
  • endothelial cells
  • induced pluripotent stem cells
  • uremic toxin
  • uremic vasculopathy

ASJC Scopus subject areas

  • Developmental Biology
  • Cell Biology

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