Nucleotide-Binding Oligomerization Domain-Like Receptor Protein 3 Deficiency in Vascular Smooth Muscle Cells Prevents Arteriovenous Fistula Failure Despite Chronic Kidney Disease
Nucleotide-Binding Oligomerization Domain-Like Receptor Protein 3 Deficiency in Vascular Smooth Muscle Cells Prevents Arteriovenous Fistula Failure Despite Chronic Kidney Disease
复制标题
血管平滑肌细胞中核苷酸结合寡聚化结构域样受体蛋白3的缺陷可预防慢性肾病的动静脉瘘失败
DOI：
10.1161/jaha.118.011211
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发表时间：
2019-01-08
影响因子：
5.4
通讯作者：
Xia, Jiahong
中科院分区：
文献类型：
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作者：
Ding, Xiangchao;Chen, Jiuling;Xia, Jiahong
背景-动静脉内瘘（AVF）是慢性肾病患者的首选血液透析途径。慢性肾脏疾病会增加新内膜的形成，从而通过未知的机制极大地导致 AVF 失败。我们的研究旨在确定核苷酸结合寡聚化结构域样受体蛋白 3 (NLRP3) 在慢性肾脏疾病的情况下实验性 AVF 诱导的新内膜形成中的作用。 方法和结果 - 根据我们的研究结果，NLRP3 在尿毒症小鼠和患者的 AVF 内膜病变中表达上调。平滑肌特异性敲除 NLRP3 小鼠表现出 AVF 流出静脉中新内膜形成显着减少。与从对照小鼠中分离的原代血管平滑肌细胞相比，从平滑肌特异性敲除NLRP3小鼠中分离的细胞表现出增殖、迁移、表型转换受损以及激活单核巨噬细胞的能力减弱。为了确定 NLRP3 的功能，使用了几种小分子抑制剂。结果表明，NLRP3 通过 Smad2/3 磷酸化而不是通过 caspase-1/interleukin-1 信号传导来调节平滑肌细胞增殖和迁移。出乎意料的是，选择性NLRP3炎性体抑制剂MCC950也能抑制Smad2/3磷酸化，并缓解慢性肾脏病促进的AVF衰竭，与巨噬细胞无关。结论——我们的研究结果表明，血管平滑肌细胞中的NLRP3可能在尿毒症相关AVF衰竭中发挥关键作用，可能是治疗AVF衰竭的一个有前途的治疗靶点。
Background-The arteriovenous fistula (AVF) is the preferred hemodialysis access for patients with chronic kidney disease. Chronic kidney disease can increase neointima formation, which greatly contributes to AVF failure by an unknown mechanism. Our study aimed to determine the role of nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) in neointima formation induced by experimental AVFs in the presence of chronic kidney disease.Methods and Results-From our findings, NLRP3 was upregulated in the intimal lesions of AVFs in both uremic mice and patients. Smooth muscle-specific knockout NLRP3 mice exhibited markedly decreased neointima formation in the outflow vein of AVFs. Compared with primary vascular smooth muscle cells isolated from control mice, those isolated from smooth muscle-specific knockout NLRP3 mice showed compromised proliferation, migration, phenotypic switching, and a weakened ability to activate mononuclear macrophages. To identify how NLRP3 functions, several small-molecule inhibitors were used. The results showed that NLRP3 regulates smooth muscle cell proliferation and migration through Smad2/3 phosphorylation rather than through caspase-1/interleukin-1 signaling. Unexpectedly, the selective NLRP3-inflammasome inhibitor MCC950 also repressed Smad2/3 phosphorylation and relieved chronic kidney disease-promoted AVF failure independent of macrophages.Conclusions-Our findings suggest that NLRP3 in vascular smooth muscle cells may play a crucial role in uremia-associated AVF failure and may be a promising therapeutic target for the treatment of AVF failure.