Spermidine protects against acute kidney injury by modulating macrophage NLRP3 inflammasome activation and mitochondrial respiration in an eIF5A hypusination-related pathway

被引:22
作者
Li, Xianzhi [1 ,2 ,3 ]
Zhou, Xiaojun [2 ,3 ]
Liu, Xigao [1 ]
Li, Xiaoyun [4 ]
Jiang, Xianzhou [1 ]
Shi, Benkang [1 ]
Wang, Shuo [1 ]
机构
[1] Shandong Univ, Dept Urol, Qilu Hosp, 107 Wenhua Xi Rd, Jinan 250012, Shandong, Peoples R China
[2] Shandong First Med Univ, Affiliated Hosp 1, Dept Endocrinol & Metabol,Shandong Inst Nephrol, Shandong Key Lab Rheumat Dis & Translat Med, Jinan 250014, Shandong, Peoples R China
[3] Shandong Prov Qianfoshan Hosp, Shandong Inst Nephrol, Shandong Key Lab Rheumat Dis & Translat Med, Jinan 250014, Peoples R China
[4] Qingdao Eighth Peoples Hosp, Dept Otolaryngol, Qingdao 266121, Peoples R China
基金
中国国家自然科学基金; 中国博士后科学基金;
关键词
Spermidine; Polyamine; Acute kidney injury; Macrophage; NLRP3; ZERO PREVENTABLE DEATHS; ISCHEMIA/REPERFUSION INJURY; INTERNATIONAL SOCIETY; REPERFUSION INJURY; DENDRITIC CELLS; LIFE-SPAN; POLYAMINES; AUTOPHAGY; ISCHEMIA; LIVER;
D O I
10.1186/s10020-022-00533-1
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Background Acute kidney injury (AKI) is still a critical problem in clinical practice, with a heavy burden for national health system around the world. It is notable that sepsis is the predominant cause of AKI for patients in the intensive care unit and the mortality remains considerably high. The treatment for AKI relies on supportive therapies and almost no specific treatment is currently available. Spermidine is a naturally occurring polyamine with pleiotropic effects. However, the renoprotective effect of spermidine and the underlying mechanism remain elusive. Methods We employed mice sepsis-induced AKI model and explored the potential renoprotective effect of spermidine in vivo with different administration time and routes. Macrophage depleting was utilized to probe the role of macrophage. In vitro experiments were conducted to examine the effect of spermidine on macrophage cytokine secretion, NLRP3 inflammasome activation and mitochondrial respiration. Results We confirmed that spermidine improves AKI with different administration time and routes and that macrophages serves as an essential mediator in this protective effect. Meanwhile, spermidine downregulates NOD-like receptor protein 3 (NLRP3) inflammasome activation and IL-1 beta production in macrophages directly. Mechanically, spermidine enhances mitochondrial respiration capacity and maintains mitochondria function which contribute to the NLRP3 inhibition. Importantly, we showed that eukaryotic initiation factor 5A (eIF5A) hypusination plays an important role in regulating macrophage bioactivity. Conclusions Spermidine administration practically protects against sepsis-induced AKI in mice and macrophages serve as an essential mediator in this protective effect. Our study identifies spermidine as a promising pharmacologic approach to prevent AKI.
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页数:17
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