NLRP3 inflammasome activation regulated by NF-κB and DAPK contributed to paraquat-induced acute kidney injury
NLRP3 inflammasome activation regulated by NF-κB and DAPK contributed to paraquat-induced acute kidney injury
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NF-kappa B 和 DAPK 调节的 NLRP3 炎症小体激活导致百草枯诱导的急性肾损伤
DOI：
10.1007/s12026-017-8901-7
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发表时间：
2017-06-01
影响因子：
4.4
通讯作者：
Zhao, Min
中科院分区：
文献类型：
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作者：
Liu, Zhenning;Wang, Xiaokai;Zhao, Min
百草枯可引起人体多器官功能障碍。然而，急性肾损伤中含核苷酸结合结构域和富含亮氨酸重复序列的蛋白3（NLRP 3）炎性小体激活的机制尚未明确。本研究的目的是确定NLRP 3炎性小体激活的作用及其通过核因子-κ B（NF-κ B）和死亡相关蛋白激酶（DAPK）的调节。雄性Wistar大鼠腹腔注射20 mg/kg百草枯，并在百草枯暴露前1 h以10 mg/kg的剂量预处理NF-κ B B抑制剂BAY 11-7082。此外，用针对DAPK的小干扰RNA（siRNA）转染大鼠肾小管上皮细胞（NRK-52 E），以评估其在NLRP 3炎性体活化中的作用。通过免疫组织化学染色或Western印迹评价DAPK和NLRP 3炎性体;通过ELISA测量促炎细胞因子，包括肿瘤坏死因子α（TNF-α）、白细胞介素-1 β（IL-1 β）和白细胞介素-18（IL-18）。结果显示，百草枯（PQ）处理后，大鼠肾脏NF-κ B、DAPK和NLRP 3炎性体被激活，促炎细胞因子分泌显著增加。NF-κ B抑制剂可减轻这些毒性作用。此外，针对DAPK的siRNA可抑制百草枯处理的大鼠肾小管上皮细胞中NLRP 3炎性体的激活以及IL-1 β和IL-18的分泌。综上所述，NF-κ B B和DAPK调控的NLRP 3炎性体活化在百草枯致急性肾损伤中起重要作用。
Paraquat can result in dysfunction of multiple organs after ingestion in human. However, the mechanisms of nucleotide-binding domain and leucine-rich repeat containing protein 3 (NLRP3) inflammasome activation in acute kidney injury have not been clearly demonstrated. The aim of this study was to determine the effect of NLRP3 inflammasome activation and its regulation by nuclear factor-kappa B (NF-kappa B) and death-associated protein kinase (DAPK). Male Wistar rats were treated with intraperitoneal injection of paraquat at 20 mg/kg, and NF-kappa B inhibitor BAY 11-7082 was pretreated at 10 mg/kg 1 h before paraquat exposure. Additionally, rat renal tubular epithelial cells (NRK-52E) were transfected with small interfering RNA (siRNA) against DAPK to evaluate its role in NLRP3 inflammasome activation. DAPK and NLRP3 inflammasome were evaluated by immunohistochemistry staining or Western blot; the pro-inflammatory cytokines including tumor necrosis factor alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), and interleukin-18 (IL-18) were measured via ELISA. The results showed that NF-kappa B, DAPK, and NLRP3 inflammasome were activated in paraquat (PQ)-treated rat kidney; the secretion of pro-inflammatory cytokines was significantly increased. These toxic effects were attenuated by NF-kappa B inhibitor. Besides, the activation of NLRP3 inflammasome and secretion of IL-1 beta and IL-18 in paraquat-treated rat renal tubular epithelial cells were inhibited by siRNA against DAPK. In conclusion, NLRP3 inflammasome activation regulated by NF-kappa B and DAPK played an important role in paraquat-induced acute kidney injury.