Uric acid induced the phenotype transition of vascular endothelial cells via induction of oxidative stress and glycocalyx shedding
Uric acid induced the phenotype transition of vascular endothelial cells via induction of oxidative stress and glycocalyx shedding
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DOI：
10.1096/fj.201901148r
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发表时间：
2019-12-01
期刊：
影响因子：
4.8
通讯作者：
Kang, Duk-Hee
中科院分区：
文献类型：
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作者：
Ko, Jiyeon;Kang, Hyun-Jung;Kang, Duk-Hee
近年来的研究表明，尿酸（UA）在肾脏疾病的发生发展中起着重要作用，而内皮功能障碍被认为是其中的关键机制。内皮细胞向间质转化（EndoMT）和糖萼脱落是内皮功能障碍的早期变化。我们研究了UA是否诱导HUVECs和高尿酸血症动物模型中的EndoMT，该动物模型用2%氧嗪酸喂养4周。UA诱导HUVECs中的EndoMT，通过激活膜NADPH氧化酶（从15 min开始）和线粒体（从6 h开始）产生活性氧，沿着糖萼脱落（从6 h开始），丙磺舒阻断了这些活性氧。基质金属蛋白酶抑制剂GM 6001可减轻UA诱导的糖萼脱落和EndoMT。抗氧化剂包括N-乙酰半胱氨酸，夹竹桃素，mitotempo改善内皮MT，但是，他们没有改变糖萼脱落在HUVEC。在高尿酸血症大鼠的肾脏中，肾小管周围毛细血管（PTC）中的内皮染色显著减少，PTC中α-平滑肌肌动蛋白重新表达。高尿酸血症大鼠血浆syndecan-1水平升高，别嘌呤醇可改善这种变化。尿酸通过诱导氧化应激和糖萼脱落引起内皮细胞表型转变，这可能是尿酸诱导内皮功能障碍和肾脏疾病的机制之一。
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 via 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 N-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 de novo expression of alpha-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 via induction of oxidative stress with glycocalyx shedding, which could be one of the mechanisms of UA-induced endothelial dysfunction and kidney disease.