The regulation of NLRP3 inflammasome expression during the development of cardiac contractile dysfunction in chronic kidney disease
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Li-Han Chin1, Yu-Juei Hsu2,3, Shih-Che Hsu3, Yen-Hui Chen4, Yung-Lung Chang3, Shih-Ming Huang3, Chien-Sung Tsai1,5 and Chih-Yuan Lin1
1Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
2Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
3Department of Biochemistry, National Defense Medical Center, Taipei, Taiwan
4Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
5Superintendent’s Office, Taoyuan Armed Forces General Hospital, Taoyuan, Taiwan
Chih-Yuan Lin, email: [email protected]
Keywords: cardiac contractile dysfunction; chronic kidney disease; uremic cardiomyopathy; NLRP3 inflammasome; apoptosis
Received: August 18, 2017 Accepted: November 09, 2017 Published: December 06, 2017
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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