Nlrp3 Deficiency Alleviates Lipopolysaccharide-Induced Acute Kidney Injury via Suppressing Renal Inflammation and Ferroptosis in Mice.
Nlrp3 Deficiency Alleviates Lipopolysaccharide-Induced Acute Kidney Injury via Suppressing Renal Inflammation and Ferroptosis in Mice.
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DOI：
10.3390/biology12091188
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发表时间：
2023-08-31
期刊：
影响因子：
4.2
通讯作者：
Ni, Xin
中科院分区：
文献类型：
--
作者：
Li, Zhilan;Wang, Xuan;Peng, Yi;Yin, Hongling;Yu, Shenyi;Zhang, Weiru;Ni, Xin
急性肾损伤是一组常见且严重的临床综合征，病因众多，包括脓毒症。脓毒症相关急性肾损伤发展的分子机制在很大程度上仍然未知，这解释了当前临床策略的局限性。NLRP3炎性小体是研究最广泛的肾脏炎性小体，在脓毒症和急性肾损伤的发病机制中起着至关重要的作用。在此，我们试图确定NLRP3在脓毒症相关急性肾损伤患者中的表达，并探讨NLRP3参与的意义和机制。根据我们的数据，脓毒症相关急性肾损伤患者肾脏中NLRP3表达上调。此外，Nlrp3缺乏显著减轻脓毒症相关的急性肾损伤。在机械上，我们发现Nlrp3敲除可以减少小鼠肾脏的炎症，逆转代谢途径的变化，并减少铁下垂。这些发现表明Nlrp3缺乏通过抑制肾炎症和铁下垂改善脓毒症相关的急性肾损伤，物质代谢调节可能对Nlrp3的功能很重要。这为NLRP3参与脓毒症相关急性肾损伤的机制提供了新的线索，并为考虑NLRP3作为治疗靶点提供了进一步的证据。核苷酸结合寡聚化结构域样受体蛋白3 （NLRP3）炎症小体是许多炎症反应的重要组成部分。本研究旨在研究NLRP3在脂多糖（LPS）诱导的脓毒症相关急性肾损伤（S-AKI）中的作用，并探讨其机制。我们首次通过免疫组织化学分析验证了S-AKI患者肾组织中NLRP3表达升高。通过LPS注射野生型和Nlrp3−/−小鼠，建立S-AKI模型。研究发现，lps诱导的肾损伤，包括组织学检查中的形态学异常、实验室检查中的肾功能异常以及AKI生物标志物表达的增加，在nlrp3缺陷小鼠中被显著逆转。Nlrp3缺失减轻了肾脏炎症，这可以通过抑制促炎细胞因子和趋化因子的表达来证明。RNA测序和FerrDb V2数据库的联合分析显示，Nlrp3敲除可调节lps诱导的S-AKI的多种代谢途径和铁凋亡。进一步的qPCR结合普鲁士蓝染色表明，敲除Nlrp3可抑制小鼠肾铁下垂，提示Nlrp3参与S-AKI发病的新机制。综上所述，上述研究结果表明Nlrp3缺乏通过减轻肾脏炎症和铁下垂来减轻lps诱导的S-AKI。我们的数据强调NLRP3是S-AKI的潜在治疗靶点。
Acute kidney injury is a common and severe group of clinical syndromes with numerous causes, including sepsis. The molecular mechanisms underlying sepsis-associated acute kidney injury development remain largely unknown, which explains the limitations of current clinical strategies. The NLRP3 inflammasome, the most widely researched inflammasome in the kidney, is crucial in the pathogenesis of sepsis and acute kidney injury. Herein, we sought to determine the expression of NLRP3 in patients with sepsis-associated acute kidney injury and investigate the significance and mechanisms of NLRP3 involvement. According to our data, patients with sepsis-associated acute kidney injury had upregulated NLRP3 expression in their kidneys. In addition, Nlrp3 deficiency strikingly attenuated sepsis-associated acute kidney injury. Mechanically, we found that Nlrp3 knockout reduced inflammation, reversed metabolic pathway changes, and decreased ferroptosis in the mouse kidneys. These findings indicate that Nlrp3 deficiency ameliorates sepsis-associated acute kidney injury via suppressing renal inflammation and ferroptosis and that substance metabolism modulation may be of importance for NLRP3 functioning. This sheds new light on the mechanisms of NLRP3 involvement in sepsis-associated acute kidney injury and provides further evidence for considering NLRP3 as a therapeutic target. The nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome is a vital component of many inflammatory responses. Here, we intended to investigate the involvement of NLRP3 in lipopolysaccharide (LPS)-induced sepsis-associated acute kidney injury (S-AKI) and explore its mechanisms. For the first time, we validated elevated NLRP3 expression in the renal tissues of S-AKI patients by immunohistochemistry analysis. Through LPS injection in both wild-type and Nlrp3−/− mice, a S-AKI model was developed. It was found that LPS-induced kidney injury, including an abnormal morphology in a histological examination, abnormal renal function in a laboratory examination, and an increase in the expression of AKI biomarkers, was dramatically reversed in Nlrp3-deficient mice. Nlrp3 deletion alleviated renal inflammation, as evidenced by the suppression of the expression of pro-inflammatory cytokines and chemokines. A combinative analysis of RNA sequencing and the FerrDb V2 database showed that Nlrp3 knockout regulated multiple metabolism pathways and ferroptosis in LPS-induced S-AKI. Further qPCR coupled with Prussian blue staining demonstrated that Nlrp3 knockout inhibited murine renal ferroptosis, indicating a novel mechanism involving S-AKI pathogenesis by NLRP3. Altogether, the aforementioned findings suggest that Nlrp3 deficiency alleviates LPS-induced S-AKI by reducing renal inflammation and ferroptosis. Our data highlight that NLRP3 is a potential therapeutic target for S-AKI.
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影响因子：
64.5
作者：
Dixon SJ;Lemberg KM;Lamprecht MR;Skouta R;Zaitsev EM;Gleason CE;Patel DN;Bauer AJ;Cantley AM;Yang WS;Morrison B 3rd;Stockwell BR
通讯作者：
Stockwell BR
影响因子：
7.3
作者：
通讯作者：
--
影响因子：
3.8
作者：
Huang, Wei;Wang, Xiaoting;Liu, Dawei
通讯作者：
Liu, Dawei
影响因子：
39.2
作者：
Levey AS;Stevens LA;Schmid CH;Zhang YL;Castro AF 3rd;Feldman HI;Kusek JW;Eggers P;Van Lente F;Greene T;Coresh J;CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration)
通讯作者：
CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration)
DOI：
10.1016/j.jsbmb.2019.04.009
发表时间：
2019-07-01
影响因子：
4.1
作者：
Chen, Lan-Sun;Singh, Sumeet Pal;Kanczkowski, Waldemar
通讯作者：
Kanczkowski, Waldemar