Li Zhilan, Wang Xuan, Peng Yi, Yin Hongling, Yu Shenyi, Zhang Weiru, Ni Xin
Department of Rheumatology and Immunology, Xiangya Hospital, Central South University, Changsha 410008, China.
Department of General Medicine, Xiangya Hospital, Central South University, Changsha 410008, China.
Biology (Basel). 2023 Aug 31;12(9):1188. doi: 10.3390/biology12091188.
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 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 -deficient mice. 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 knockout regulated multiple metabolism pathways and ferroptosis in LPS-induced S-AKI. Further qPCR coupled with Prussian blue staining demonstrated that knockout inhibited murine renal ferroptosis, indicating a novel mechanism involving S-AKI pathogenesis by NLRP3. Altogether, the aforementioned findings suggest that 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.
核苷酸结合寡聚化结构域样受体蛋白3（NLRP3）炎性小体是许多炎症反应的重要组成部分。在此，我们旨在研究NLRP3在脂多糖（LPS）诱导的脓毒症相关性急性肾损伤（S-AKI）中的作用，并探讨其机制。我们首次通过免疫组化分析验证了S-AKI患者肾组织中NLRP3表达升高。通过向野生型和[此处原文缺失相关小鼠类型信息]小鼠注射LPS，建立了S-AKI模型。结果发现，LPS诱导的肾损伤，包括组织学检查中的形态异常、实验室检查中的肾功能异常以及AKI生物标志物表达增加，在[此处原文缺失相关基因缺失小鼠类型信息]基因缺陷小鼠中得到显著逆转。[此处原文缺失相关基因缺失小鼠类型信息]基因缺失减轻了肾脏炎症，促炎细胞因子和趋化因子表达的抑制证明了这一点。RNA测序与FerrDb V2数据库的联合分析表明，[此处原文缺失相关基因缺失小鼠类型信息]基因敲除调节了LPS诱导的S-AKI中的多种代谢途径和铁死亡。进一步的qPCR结合普鲁士蓝染色表明，[此处原文缺失相关基因缺失小鼠类型信息]基因敲除抑制了小鼠肾脏铁死亡，提示NLRP3参与S-AKI发病机制的新机制。总之，上述发现表明，[此处原文缺失相关基因缺失小鼠类型信息]基因缺陷通过减轻肾脏炎症和铁死亡来缓解LPS诱导的S-AKI。我们的数据突出了NLRP3是S-AKI的潜在治疗靶点。
