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

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

Author information

1
Dept. of Nephrology, Daping Hospital, Research Institute of Surgery, the Third Military Medical Univ., Chongqing 400042, China. heynmail@yahoo.com.

Abstract

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

Comment in

PMID:
24133119
DOI:
10.1152/ajprenal.00117.2013
[Indexed for MEDLINE]
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