Caspase-11-mediated tubular epithelial pyroptosis underlies contrast-induced acute kidney injury

• Published in: Cell death & disease Vol. 9; no. 10; pp. 983 - 13
• Main Authors: Zhang, Zhen, Shao, Xinghua, Jiang, Na, Mou, Shan, Gu, Leyi, Li, Shu, Lin, Qisheng, He, Yipei, Zhang, Minfang, Zhou, Wenyan, Ni, Zhaohui
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 24.09.2018; Springer Nature B.V
• Subjects: 13; 13/51; 13/89; 59; 82; 82/80; Acute Kidney Injury - chemically induced; Animals; Antibodies; Apoptosis; Biochemistry; Biomedical and Life Sciences; Caspase; Caspase-11; Caspase-4; Caspases - genetics; Caspases - metabolism; Caspases, Initiator - genetics; Caspases, Initiator - metabolism; Cell Biology; Cell Culture; Cell death; Cells, Cultured; Clonal deletion; Contrast agents; Contrast media; Contrast Media - adverse effects; Disease Models, Animal; Epithelial cells; Epithelial Cells - metabolism; Gene Knockdown Techniques; Humans; IL-1β; Immunology; Inflammation; Inflammation - metabolism; Interleukin-1beta - metabolism; Intracellular Signaling Peptides and Proteins - metabolism; Iohexol - adverse effects; Kidney Tubules - pathology; Kidneys; Life Sciences; Male; Mice; Mice, Inbred C57BL; Phosphate-Binding Proteins - metabolism; Pyroptosis; Pyroptosis - drug effects; Renal failure; Therapeutic applications; Tubules
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-018-1023-x

Contrast-induced acute kidney injury (CI-AKI) is a serious complication in patients after administration of iodinated contrast media and is associated with a significant high risk for severe renal failure and death due to the wholesale necrosis of the tubules and interstitial inflammation. Pyroptosis is a form of programmed lytic cell death that is triggered by inflammatory caspases, but little is known about its role in tubular epithelial cell (TEC) death and contrast-induced acute kidney injury. Here we show that systemic exposure to contrast media causes severe tubular epithelial pyroptosis that is mediated by the inflammatory caspases, caspases 4/5 in human TECs, or the murine homolog caspase-11 in mice in vivo and in mouse TECs in vitro. Knockdown of caspase-4/5 preserved human TECs from cell death and reduced the release of mature IL-1β, and in caspase-11-deficient mice, contrast-induced acute kidney injury was abrogated, indicating a central role for caspase-11 in acute kidney injury. In addition, deletion of caspase-11 in TECs reduced Gsdmd cleavage, which is the key process for execution of pyroptosis. These results establish the requisite role of epithelial pyroptosis in contrast-induced acute kidney injury and suggest that epithelial inflammatory caspases are an important therapeutic target for acute kidney injury.