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

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Abstract

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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Abbreviations

PQ:

Paraquat

NLRP3:

Nucleotide-binding domain and leucine-rich repeat containing protein 3

ASC:

Apoptosis-associated speck-like protein containing caspase-1 activator domain

IL-1β:

Interleukin-1β

IL-18:

Interleukin-18

TNF-α:

Tumor necrosis factor

ROS:

Reactive oxygen species

LDH:

Lactate dehydrogenase

NF-κB:

Nuclear factor-kappa B

DAPK:

Death-associated protein kinase

BUN:

Blood urea nitrogen

SOD:

Superoxide dismutase

CAT :

Catalase

COX-2:

Cyclooxygenase-2

iNOS:

Nitric oxide synthase

KIM-1:

Kidney injury molecule-1

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Acknowledgments

This study was supported by the National Natural Science Foundation of China (Grant No. 81601673) and Science Research Plan of Liaoning Province Education Administration (Grant No. L2014300).

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Authors and Affiliations

  1. Department of Emergency Medicine, Shengjing Hospital of China Medical University, No. 36, Sanhao Street, Heping District, Shenyang, 110004, China

    Zhenning Liu, Yu Wang & Min Zhao

  2. Department of Pathology, The General Hospital of Shenyang Military, No. 83, Wenhua Road, Shenhe District, Shenyang, 110016, China

    Xiaokai Wang

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  1. Zhenning Liu
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Correspondence to Min Zhao.

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Liu, Z., Wang, X., Wang, Y. et al. NLRP3 inflammasome activation regulated by NF-κB and DAPK contributed to paraquat-induced acute kidney injury. Immunol Res 65, 687–698 (2017). https://doi.org/10.1007/s12026-017-8901-7

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