Abstract
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.
Highlights
Acute renal failure, the most severe form of acute kidney injury (AKI), is a devastating clinical complication of contrast-induced AKI (CI-AKI), which is usually defined as a rise in serum creatinine (SCr) of ≥ 0.5 mg/dl (≥44 μmol/l) or a 25% increase from baseline value, assessed within 48–72 h after a radiological procedure without an alternative etiology[1]
To identify the underlying mechanism, we investigated the role of the inflammatory caspase-11 in mouse tubular epithelial cell (TEC) and caspase-4/5 in human TECs
We observed basal expression of caspase-11 in mouse TECs and caspase-4/5 in human TECs, and they were markedly upregulated by iohexol incubation for 72 h (Fig. 1b); the effect was more prominent with caspase-5 (Fig. 1c)
Summary
The most severe form of acute kidney injury (AKI), is a devastating clinical complication of contrast-induced AKI (CI-AKI), which is usually defined as a rise in serum creatinine (SCr) of ≥ 0.5 mg/dl (≥44 μmol/l) or a 25% increase from baseline value, assessed within 48–72 h after a radiological procedure without an alternative etiology[1]. AKI is characterized by an exaggerated host-defense immune response and necrotic tubular epithelial cells (TECs) loss of function, and is frequently the source of damage-. The epithelial cells are invariably exposed to the toxic drugs such as contrast media, which are key for the pathogenesis of CI-AKI3,5. Renal TEC damage or death occurs and DAMPs, released by dead TECs, triggers a host-defense immune response and release of proinflammatory cytokines such as interleukin (IL)-1β4. Moderate immune-inflammatory response in the kidney is an Official journal of the Cell Death Differentiation Association
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