Combination exposure of melamine and cyanuric acid is associated with polyuria and activation of NLRP3 inflammasome in rats
Combination exposure of melamine and cyanuric acid is associated with polyuria and activation of NLRP3 inflammasome in rats
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三聚氰胺和三聚氰酸的联合暴露与大鼠多尿和 NLRP3 炎症小体的激活有关
DOI：
10.1152/ajprenal.00609.2017
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Li Chunling
中科院分区：
文献类型：
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作者：
Wang Feifei;Liu Qiaojuan;Jin Lizi;Hu Shan;Luo Renfei;Han Mengke;Zhai Yonggong;Wang Weidong;Li Chunling
三聚氰胺诱导肾毒性的分子机制尚未完全清楚。本研究的目的是研究三聚氰胺和氰尿酸是否诱导肾脏中NOD样受体家族含吡林结构域3（NLRP 3）炎性小体激活，这可能导致大鼠模型中水和钠处理异常。Wistar大鼠分别给予三聚氰胺（Mel; 200 mg·kg·d-1）、三聚氰酸（CA; 200 mg·kg·d-1）或Mel + CA（Mel + CA;各100 mg·kg·d-1）2周。Mel + CA可引起肾小管上皮细胞结构和细胞器损伤、管腔扩张和炎症反应。在尿液和血清标本中观察到晶体，也在扩张的远端肾小管管腔中观察到晶体。Mel和CA联合给药后，大鼠尿中Mel和CA浓度明显降低，这与内髓水通道蛋白（AQP）1、2和3以及皮质和外髓α-Na-K-ATP酶和Na-K-2Cl转运体蛋白表达减少有关。Mel + CA处理与肾脏中CD 3的蛋白表达和CD 68和F4/80的mRNA水平以及NF-κB的磷酸化增加相关。Mel + CA处理增加了大鼠内髓中含有半胱天冬酶募集结构域的NLRP 3炎性体组分骨化相关斑点样蛋白、半胱天冬酶-1和IL-1β的蛋白和mRNA表达。NF-κB抑制剂Bay 11-7082可抑制Mel + CA诱导的内髓集合管细胞IL-1β表达，并阻止AQP 2的下调。总之，Mel + CA处理引起尿浓缩缺陷和肾AQP和关键钠转运蛋白的表达降低，这可能是由于肾脏中形成的晶体诱导的炎症反应和NLRP 3炎性体的激活。
The molecular mechanisms of melamine-induced renal toxicity have not been fully understood. The purpose of the study aimed to investigate whether melamine and cyanuric acid induced NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activation in the kidney, which may contribute to abnormal water and sodium handling in a rat model. Wistar rats received melamine (Mel; 200 mg·kg body wt−1·day−1), cyanuric acid (CA; 200 mg·kg body wt−1·day−1), or Mel plus CA (Mel + CA; 100 mg·kg body wt−1·day−1, each) for 2 wk. Mel + CA caused damaged tubular epithelial structure and organelles, dilated tubular lumen, and inflammatory responses. Crystals were observed in urine and serum specimen, also in the lumen of dilated distal renal tubules. The combined ingestion of Mel and CA in rats caused a markedly impaired urinary concentration, which was associated with reduced protein expression of aquaporin (AQP)1, 2, and 3 in inner medulla and α-Na-K-ATPase and Na-K-2Cl transporters in cortex and outer medulla. Mel + CA treatment was associated with increased protein expression of CD3 and mRNA levels of CD68 and F4/80 as well as phosphorylation of NF-κB in the kidney. Mel + CA treatment increased protein and mRNA expression of NLRP3 inflammasome components apoptosis-associated speck-like protein containing a caspase recruitment domain, caspase-1, and IL-1β in the inner medulla of rats. NF-κB inhibitor Bay 11-7082 reduced IL-1β expression induced by Mel + CA and prevented downregulation of AQP2 in inner medullary collecting duct cell suspensions. In conclusion, Mel + CA treatment caused urinary-concentrating defects and reduced expression of renal AQPs and key sodium transporters, which is likely due to the inflammatory responses and activation of NLRP3 inflammasome induced by crystals formed in the kidney.