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
Division of Nephrology, Department of Medicine, Samsung Medical Center, Stem Cell & Regenerative Medicine Institute(SCRMI), Sungkyunkwan University School of Medicine, Seoul, South Korea.
School for Engineering of Matter, Transport & Energy, Arizona State University, Tempe, AZ, United States.
Front Cell Dev Biol. 2021 Jan 12;8:618796. doi: 10.3389/fcell.2020.618796. eCollection 2020.
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. In this study, we aimed to develop a novel model of uremic vasculopathy as a potential drug screening system. 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. 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.
心血管并发症是慢性肾脏病（CKD）患者死亡的主要原因。尿毒症血管病变在晚期CKD患者心血管并发症的进展中起着关键作用。然而，传统研究方法的改进可以为CKD提供进一步的见解。在本研究中，我们旨在开发一种新型的尿毒症血管病变模型，作为一种潜在的药物筛选系统。使用多种功能测定方法，研究了尿毒症血清和不同组合的尿毒症毒素对正常对照和CKD患者的诱导多能干细胞（iPSC）衍生的内皮细胞（ECs）的影响。我们发现，由高尿素、肌酐、尿酸和硫酸吲哚酚组成的尿毒症毒素混合物通过增加活性氧和细胞凋亡以及抑制管形成，对正常对照iPSC-ECs产生了与尿毒症血清相当的有害影响。进一步的表征显示，TGF-β信号失调可能参与其中，因为用氯沙坦或TGF-β抑制剂治疗可减轻尿毒症毒素诱导的不良反应。重要的是，氯沙坦和TGF-β抑制剂治疗可挽救CKD患者特异性iPSC-ECs中受损的伤口愈合潜力。我们的研究表明，简化的尿毒症毒素混合物可以可重复地模拟尿毒症微环境，CKD患者特异性iPSC-ECs可以潜在地概括对尿毒症血管病变的易感性。这种新型的尿毒症血管病变模型可能作为一种药物筛选系统提供一种新的研究工具。
