The regulation of NLRP3 inflammasome expression during the development of cardiac contractile dysfunction in chronic kidney disease.
The regulation of NLRP3 inflammasome expression during the development of cardiac contractile dysfunction in chronic kidney disease.
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DOI：
10.18632/oncotarget.22964
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发表时间：
2017-12-26
期刊：
影响因子：
--
通讯作者：
Lin CY
中科院分区：
文献类型：
--
作者：
Chin LH;Hsu YJ;Hsu SC;Chen YH;Chang YL;Huang SM;Tsai CS;Lin CY
慢性炎症在慢性肾脏病(CKD)患者的长期并发症中起着至关重要的作用。本研究旨在探讨NLRP3炎性小体在慢性肾脏病心脏收缩功能障碍中的作用。在假手术和5/6肾切除的CKD小鼠模型中，观察心脏收缩功能和NLRP3炎症体及相关细胞因子的表达。在体外，用尿毒症毒素吲哚硫酸盐(IS)处理H9c2细胞，通过小干扰RNA(SiRNA)介导的NLRP3基因敲除来实现对NLRP3炎性小体的抑制。此外，还检测了IS处理的H9c2细胞中核因子κB(NF-κB)信号的激活和凋亡标志物的水平。结果表明，慢性肾衰可导致体内心脏收缩功能障碍，并伴随NLRP3炎症体、IL-1β、IL-18的上调，并参与心肌细胞的凋亡。体外实验表明，IS可通过激活NF-κB信号通路上调H9c2细胞炎症体、IL-1β和IL-18水平，促进细胞凋亡。SiNLRP3基因转染细胞后，IL-1β、IL-18水平降低，细胞凋亡率降低。此外，IL-1β或IL-18中和抗体可减轻IS引起的细胞活力下降。综上所述，慢性肾功能不全可导致心脏收缩功能障碍，与尿毒症毒素诱导的NLRP3炎性小体/IL-1β/IL-18轴上调有关。
Chronic inflammation plays a crucial role in the long-term complications in patients with chronic kidney disease (CKD). This study aimed to assess the role of NLR pyrin domain-containing protein (NLRP3) inflammasome in cardiac contractile dysfunctions in CKD. The cardiac contractile function was evaluated and the expression of NLRP3 inflammasome and related cytokines in the heart was assessed in a murine sham-operated and 5/6 nephrectomy CKD model in vivo. In vitro, H9c2 cells were treated with uremic toxin indoxyl sulfate (IS), with or without NLRP3 inflammasome inhibition, which was achieved by using small interfering RNA (siRNA)-mediated knockdown of the NLRP3 gene. Moreover, the activation of nuclear factor κB (NF-κB) signaling and apoptosis marker levels were assessed in the IS-treated H9c2 cells. The results demonstrated that CKD can lead to the development of cardiac contractile dysfunction in vivo associated with the upregulation of NLRP3 inflammasome, IL-1β, IL-18, and contribute to the myocardial apoptosis. In vitro experiments showed the upregulation of inflammasome, IL-1β, and IL-18 levels, and cell apoptosis in the IS-treated H9c2 cells through the activation of NF-κB signaling pathway. The transfection of cells with si-NLRP3 was shown to alleviate IL-1β, IL-18, and cell apoptosis. Moreover, decreased cell viability induced by IS was shown to be attenuated by IL-1β or IL-18-neutralizing antibody. In summary, CKD can result in the development of cardiac contractile dysfunction associated with the upregulation of NLRP3 inflammasome/IL-1β/IL-18 axis induced by the uremic toxins.
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