NLRP3 inflammasome activation regulated by NF-κB and DAPK contributed to paraquat-induced acute kidney injury

Zhenning Liu, Xiaokai Wang, Yu Wang, Min Zhao
Immunologic Research 2017, 65 (3): 687-698
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-κB) and death-associated protein kinase (DAPK). Male Wistar rats were treated with intraperitoneal injection of paraquat at 20 mg/kg, and NF-κB 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 α (TNF-α), interleukin-1β (IL-1β), and interleukin-18 (IL-18) were measured via ELISA. The results showed that NF-κB, 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-κB inhibitor. Besides, the activation of NLRP3 inflammasome and secretion of IL-1β 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-κB and DAPK played an important role in paraquat-induced acute kidney injury.

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