title: Ischemia-reperfusion induces renal tubule pyroptosis via the CHOP-caspase-11 pathway.
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.
authors.affiliation: Dept. of Nephrology, Daping Hospital, Research Institute of Surgery, the Third Military Medical Univ., Chongqing 400042, China. heynmail@yahoo.com.
authors.forename: Ju-Rong
authors.initials: JR
authors.lastname: Yang
authors.forename: Feng-Hua
authors.initials: FH
authors.lastname: Yao
authors.forename: Jian-Guo
authors.initials: JG
authors.lastname: Zhang
authors.forename: Zhi-Yong
authors.initials: ZY
authors.lastname: Ji
authors.forename: Kai-Long
authors.initials: KL
authors.lastname: Li
authors.forename: Jun
authors.initials: J
authors.lastname: Zhan
authors.forename: Yu-Na
authors.initials: YN
authors.lastname: Tong
authors.forename: Li-Rong
authors.initials: LR
authors.lastname: Lin
authors.forename: Ya-Ni
authors.initials: YN
authors.lastname: He
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D020169:Caspases / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D015971:Gene Expression Regulation, Enzymologic; D055785:Gene Knockdown Techniques; D000860:Hypoxia; D007684:Kidney Tubules / Q000166:cytology / Q000201:enzymology / Q000502:physiology*; D008297:Male; D034622:RNA Interference; D034741:RNA, Small Interfering; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury; D013312:Stress, Physiological; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism*
chemical_list: C497251:Ddit3 protein, rat; D034741:RNA, Small Interfering; D051742:Transcription Factor CHOP; C491071:Casp4 protein, rat; D020169:Caspases
keywords: C/EBP homologous protein; caspase-11; endoplasmic reticulum stress; pyroptosis; renal ischemia-reperfusion injury