Division of Nephrology, Department of Internal Medicine, Ewha Medical Research Center, College of Medicine, Ewha Womans University, Seoul, South Korea.
Department of Biotechnology, CHA University, Seongnam, South Korea.
FASEB J. 2019 Dec;33(12):13334-13345. doi: 10.1096/fj.201901148R. Epub 2019 Sep 25.
Recent data suggested a causative role of uric acid (UA) in the development of renal disease, in which endothelial dysfunction is regarded as the key mechanism. Endothelial-to-mesenchymal transition (EndoMT) and shedding of the glycocalyx are early changes of endothelial dysfunction. We investigated whether UA induced EndoMT in HUVECs and an animal model of hyperuricemia fed with 2% oxonic acid for 4 wk. UA induced EndoMT in HUVECs with a generation of reactive oxygen species the activation of membranous NADPH oxidase (from 15 min) and mitochondria (from 6 h) along with glycocalyx shedding (from 6 h), which were blocked by probenecid. GM6001, an inhibitor of matrix metalloproteinase, alleviated UA-induced glycocalyx shedding and EndoMT. Antioxidants including acetyl cysteine, apocynin, and mitotempo ameliorated EndoMT; however, they did not change glycocalyx shedding in HUVECs. In the kidney of hyperuricemic rats, endothelial staining in peritubular capillaries (PTCs) was substantially decreased with a expression of α-smooth muscle actin in PTCs. Plasma level of syndecan-1 was increased in hyperuricemic rats, which was ameliorated by allopurinol. UA caused a phenotypic transition of endothelial cells induction of oxidative stress with glycocalyx shedding, which could be one of the mechanisms of UA-induced endothelial dysfunction and kidney disease.-Ko, J., Kang, H.-J., Kim, D.-A., Kim, M.-J., Ryu, E.-S., Lee, S., Ryu, J.-H., Roncal, C., Johnson, R. J., Kang, D.-H. Uric acid induced the phenotype transition of vascular endothelial cells induction of oxidative stress and glycocalyx shedding.
最近的数据表明，尿酸（UA）在肾脏疾病的发展中起因果作用，其中内皮功能障碍被认为是关键机制。内皮-间充质转化（EndoMT）和糖萼脱落是内皮功能障碍的早期变化。我们研究了尿酸是否会在高尿酸血症动物模型中诱导 HUVECs 的 EndoMT，该动物模型在 2%草酸盐喂养 4 周。尿酸在 HUVECs 中诱导 EndoMT，同时伴随着活性氧的产生膜 NADPH 氧化酶的激活（从 15 分钟开始）和线粒体（从 6 小时开始），以及糖萼脱落（从 6 小时开始），这些都被丙磺舒阻断。基质金属蛋白酶抑制剂 GM6001 减轻了尿酸诱导的糖萼脱落和 EndoMT。抗氧化剂包括乙酰半胱氨酸、阿朴肉桂酸和 mitotempo 改善了 EndoMT；然而，它们并没有改变 HUVECs 中的糖萼脱落。在高尿酸血症大鼠的肾脏中，肾小管周围毛细血管（PTCs）中的内皮染色明显减少，PTCs 中的α-平滑肌肌动蛋白表达增加。高尿酸血症大鼠的 syndecan-1 血浆水平升高，别嘌醇可改善这一情况。尿酸导致内皮细胞表型转化诱导氧化应激伴糖萼脱落，这可能是尿酸诱导内皮功能障碍和肾脏疾病的机制之一。-Ko，J.，Kang，H.-J.，Kim，D.-A.，Kim，M.-J.，Ryu，E.-S.，Lee，S.，Ryu，J.-H.，Roncal，C.，Johnson，R. J.，Kang，D.-H.尿酸诱导血管内皮细胞表型转化诱导氧化应激和糖萼脱落。
