Modeling Uremic Vasculopathy With Induced Pluripotent Stem Cell-Derived Endothelial Cells as a Drug Screening System.
Modeling Uremic Vasculopathy With Induced Pluripotent Stem Cell-Derived Endothelial Cells as a Drug Screening System.
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用诱导多能干细胞衍生内皮细胞模拟尿毒症血管病变作为药物筛选系统。
DOI：
10.3389/fcell.2020.618796
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发表时间：
2020
影响因子：
5.5
通讯作者：
Kim YG
中科院分区：
文献类型：
--
作者：
Jang HR;Cho HJ;Zhou Y;Shao NY;Lee K;Le HHT;Jeon J;Lee JE;Huh W;Ong SG;Lee WH;Kim YG
背景：心血管并发症是慢性肾脏病（CKD）患者死亡的主要原因。尿毒症血管病变在促进晚期CKD心血管并发症的进展方面发挥着至关重要的作用。然而，传统研究方法的改进可以为CKD提供进一步的见解。目的：在这项研究中，我们的目的是建立一个新的模型，尿毒症血管病变作为一个潜在的药物筛选系统。方法和结果：尿毒症血清和尿毒症毒素的不同组合对正常对照和CKD患者的诱导多能干细胞（iPSC）衍生的内皮细胞（EC）的影响使用几种功能测定进行了研究。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的混合物对正常对照iPSC-EC产生有害影响，其通过增加活性氧和凋亡以及抑制管形成而与尿毒症血清相当。额外的表征揭示了TGF-β信号转导失调的潜在参与，因为用氯沙坦或TGF-β抑制剂治疗导致尿毒症毒素诱导的不良反应减弱。重要的是，在CKD患者特异性iPSC-EC中观察到的受损的伤口愈合潜力通过氯沙坦和TGF-β抑制剂治疗而得到挽救。结论：我们的研究表明，简化的尿毒症毒素混合物可以再现地模拟尿毒症微环境，并且CKD患者特异性iPSC-EC可以潜在地再现对尿毒症血管病变的易感性。这种新的尿毒症血管病变模型可能作为药物筛选系统提供一种新的研究工具。
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.
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影响因子：
4.6
作者：
Kim-Mitsuyama S;Soejima H;Yasuda O;Node K;Jinnouchi H;Yamamoto E;Sekigami T;Ogawa H;Matsui K
通讯作者：
Matsui K
DOI：
10.1007/978-1-62703-511-8_7
发表时间：
2013
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
--
作者：
Churko JM;Burridge PW;Wu JC
通讯作者：
Wu JC
影响因子：
1.6
作者：
Jourde-Chiche, Noemie;Dou, Laetitia;Brunet, Philippe
通讯作者：
Brunet, Philippe
影响因子：
3.3
作者：
Bal, Guerkan;Kamhieh-Milz, Julian;Salama, Abdulgabar
通讯作者：
Salama, Abdulgabar
DOI：
10.1159/000321750
发表时间：
2011-01-01
期刊：
HEMODIAFILTRATION: A NEW ERA
影响因子：
--
作者：
Glorieux, Griet;Vanholder, Raymond
通讯作者：
Vanholder, Raymond