Ischemia-reperfusion induces renal tubule pyroptosis via the CHOP-caspase-11 pathway

Am J Physiol Renal Physiol. 2014 Jan 1;306(1):F75-84. doi: 10.1152/ajprenal.00117.2013. Epub 2013 Oct 16.


The apoptotic or necrotic death of renal tubule epithelial cells is the main pathogenesis of renal ischemia-reperfusion-induced acute kidney injury (AKI). Pyroptosis is a programmed cell death pathway that depends on the activation of the caspase cascade and IL-1 cytokine family members. However, the role of pyroptosis in AKI induced by ischemia-reperfusion remains unclear. In this study, we found that the levels of the pyroptosis-related proteins, including caspase-1, caspase-11, and IL-1β, were significantly increased after 6 h of renal ischemia-reperfusion injury (IRI) and peaked at 12 h after IRI. Enhanced pyroptosis was accompanied by elevated renal structural and functional injury. Similarly, hypoxia-reoxygenation injury (HRI) also induced pyroptosis in renal tubule epithelial NRK-52E cells, which was characterized by increased pore formation and elevated lactate dehydrogenase release. In addition, obvious upregulation of the endoplasmic reticulum (ER) stress biomarkers glucose-regulated protein 78 and C/EBP homologous protein (CHOP) preceded the incidence of pyroptosis in cells treated with IRI or HRI. Pretreatment with a low dose of tunicamycin, an inducer of ER stress, relieved IRI-induced pyroptosis and renal tissue injury. Silencing of CHOP by small interfering RNA significantly decreased HRI-induced pyroptosis of NRK-52E cells, as evidenced by reduced caspase-11 activity and IL-1β generation. Therefore, we conclude that pyroptosis of renal tubule epithelial cells is a key event during IRI and that CHOP-caspase-11 triggered by overactivated ER stress may be an essential pathway involved in pyroptosis.

Keywords: C/EBP homologous protein; caspase-11; endoplasmic reticulum stress; pyroptosis; renal ischemia-reperfusion injury.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / physiology*
  • Caspases / genetics
  • Caspases / metabolism*
  • Cell Line
  • Gene Expression Regulation, Enzymologic
  • Gene Knockdown Techniques
  • Hypoxia
  • Kidney Tubules / cytology
  • Kidney Tubules / enzymology
  • Kidney Tubules / physiology*
  • Male
  • RNA Interference
  • RNA, Small Interfering
  • Random Allocation
  • Rats
  • Rats, Sprague-Dawley
  • Reperfusion Injury*
  • Stress, Physiological
  • Transcription Factor CHOP / genetics
  • Transcription Factor CHOP / metabolism*


  • Ddit3 protein, rat
  • RNA, Small Interfering
  • Transcription Factor CHOP
  • Casp4 protein, rat
  • Caspases