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Kir6.2 knockout aggravates lipopolysaccharide-induced mouse liver injury via enhancing NLRP3 inflammasome activation

  • Original Article—Liver, Pancreas, and Biliary Tract
  • Published:
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Abstract

Background

ATP-sensitive potassium (K-ATP) channels couple cellular metabolism to electric activity. Although Kir6.2-composed K-ATP channel (Kir6.2/K-ATP channel) has been demonstrated to regulate inflammation, a common cause of most liver diseases, its role in liver injury remains elusive.

Methods

Kir6.2 knockout mice were used to prepared LPS-induced liver injury model so as to investigate the role of Kir6.2/K-ATP channels in the injury. Histochemistry was applied to evaluate the extent of liver injury. Proinflammatory cytokines were analyzed by ELISA. Endoplasmic reticulum (ER) stress and autophagy were assessed by western blotting.

Results

We showed that Kir6.2 knockout markedly promoted the infiltration of lymphocytes and neutrophils in liver and significantly elevated serum levels of alanine transaminase (ALT) in respond to LPS treatment. We further found that Kir6.2 deficiency enhanced the activation of NF-κB and NLRP3 inflammasome following LPS challenge, and thereby increased the levels of pro-inflammatory cytokines IL-1β, IL-18 and TNF-α. Treatment of wild-type mice with the K-ATP channel opener iptakalim (IPT) could protect against LPS-induced liver injury through attenuating NLRP3 inflammasome-mediated inflammatory responses. Furthermore, Kir6.2 knockout-induced activation of NLRP3 inflammasome aggravated endoplasmic reticulum (ER) stress, autophagy and subsequent hepatocyte death.

Conclusion

Kir6.2 deficiency exacerbated LPS-induced liver injury by enhancing NLRP3 inflammasome-mediated inflammatory response. Thus, Kir6.2/K-ATP channel may be a potential candidate target for the treatment and prevention of liver injury.

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Acknowledgments

This work was supported by the grant from the National Key Program of Basic Research of China (No. 2009CB521906 and No. 2011CB504103), the National Natural Science Foundation of China (No. 81030060), and the National Science & Technology Major Project (No. 2012ZX09304-001). We are grateful to Drs. Susumu Seino and Takashi Miki, Kobe University, for generous donation of Kir6.2 knockout mice.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Pharmacology, Nanjing Medical University, 140 Hanzhong Road, Nanjing, 210029, Jiangsu, People’s Republic of China

    Ren-Hong Du, Jun Tan, Nan Yan, Ling Wang, Chen Qiao, Jian-Hua Ding, Ming Lu & Gang Hu

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Correspondence to Gang Hu.

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Du, RH., Tan, J., Yan, N. et al. Kir6.2 knockout aggravates lipopolysaccharide-induced mouse liver injury via enhancing NLRP3 inflammasome activation. J Gastroenterol 49, 727–736 (2014). https://doi.org/10.1007/s00535-013-0823-0

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  • DOI: https://doi.org/10.1007/s00535-013-0823-0

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