Hye Ryoun Jang1, Hyung Joon Cho2, Yang Zhou3, Ning-Yi Shao4, Kyungho Lee1, Hoai Huong Thi Le5, Junseok Jeon1, Jung Eun Lee1, Wooseong Huh1, Sang-Ging Ong6,7, Won Hee Lee5, Yoon-Goo Kim1. 1. 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, AZ, United States. 3. Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, United States. 4. Health Sciences, University of Macau, Macau, China. 5. Department of Basic Medical Sciences, University of Arizona College of Medicine, Phoenix, AZ, United States. 6. Department of Pharmacology & Regenerative Medicine, University of Illinois College of Medicine, Chicago, IL, United States. 7. Division of Cardiology, Department of Medicine, University of Illinois College of Medicine, Chicago, IL, United States.
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.
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.
Authors: Diana Lanza; Alessandra F Perna; Adriana Oliva; Raymond Vanholder; Anneleen Pletinck; Salvatore Guastafierro; Annarita Di Nunzio; Carmela Vigorito; Giovambattista Capasso; Vera Jankowski; Joachim Jankowski; Diego Ingrosso Journal: PLoS One Date: 2015-01-30 Impact factor: 3.240
Authors: Yingyao Zhou; Bin Zhou; Lars Pache; Max Chang; Alireza Hadj Khodabakhshi; Olga Tanaseichuk; Christopher Benner; Sumit K Chanda Journal: Nat Commun Date: 2019-04-03 Impact factor: 14.919
Authors: Marina P C Maires; Krislley R Pereira; Everidiene K V B Silva; Victor H R Souza; Flavio Teles; Paulyana F Barbosa; Margoth R Garnica; Felipe M Ornellas; Irene L Noronha; Camilla Fanelli Journal: Stem Cells Int Date: 2022-03-25 Impact factor: 5.443