Endotoxemic acute renal failure is attenuated in caspase-1-deficient mice

Abstract

Caspase-1-deficient (Ϫ/Ϫ) mice are protected against sepsis-induced hypotension and mortality. We investigated the role of caspase-1 and its associated cytokines in a nonhypotensive model of endotoxemic acute renal failure (ARF). Mice were injected intraperitoneally with 2.5 mg of LPS that induces endotoxemic ARF. On immunoblot analysis of whole kidney, there was an increase in caspase-1 protein in LPS-treated mice compared with vehicle-treated controls. In LPStreated mice, the glomerular filtration rate (GFR) was significantly higher in caspase-1 Ϫ/Ϫ vs. wild-type mice at 16 and 36 h after LPS. To determine the mechanism of this protection, the caspase-1-activated cytokines IL-1␤ and IL-18 were investigated. IL-1␤ and IL-18 protein were significantly increased in the kidneys of LPS-vs. vehicle-treated mice. To determine the role of these cytokines, mice were treated with recombinant IL-1 receptor antagonist (IL-1Ra) or IL-18-neutralizing antiserum. In LPS-treated mice, GFR was not different in IL-1Ra-treated or IL-18-neutralizing antiserum-treated or combination therapy (IL-1Ra plus IL-18-neutralizing antiserumtreated) compared with control mice. In addition, tubular cell apoptosis, neutrophil infiltration, myeloperoxidase activity, caspase-3 activity, and calpain activity were not different between wild-type and caspase-1 Ϫ/Ϫ mice with endotoxemic ARF. In LPS-vs. vehicletreated wild-type mice, renal IL-1␣ was significantly increased. In both LPS-and vehicle-treated caspase-1 Ϫ/Ϫ mice, renal IL-1␣ was very low. In summary, caspase-1 Ϫ/Ϫ mice are functionally protected against endotoxemic ARF. Neutralization of IL-1␤ and IL-18 is not functionally protective. The role of the intracellular proinflammatory cytokine IL-1␣ in endotoxemic ARF merits further study. glomerular filtration rate; multiorgan failure; cytokine SEPSIS IS THE COMMONEST CAUSE of acute renal failure (ARF) in the intensive care unit (2, 24). In patients with ARF, mortality is higher in patients with sepsis compared with patients without sepsis (29,30). While the presence of multiorgan failure and other comorbidities contributes to the high mortality, ARF independently increases mortality (21). The pathogenesis of endotoxemic ARF is poorly understood (3, 36). During sepsis, a broad array of humoral mediators are released into the systemic circulation including cytokines (3). Continuous venovenous hemofiltration has been advocated as the renal replacement therapy of choice in septic ARF because of the potential for cytokine removal (15,31,32). We recently demonstrated the role of tumor necrosis factor (TNF) independent of inducible nitric oxide synthase in endotoxemic ARF in mice (19). However, the role of cytokines produced in the kidney in endotoxemic ARF has not been widely investigated.The proinflammatory caspase-1 (formerly known as interleukin-1-converting enzyme or ICE) plays a major role in the cleavage of the precursor forms of the cytokines IL-1␤ and IL-18. Caspase-1 is remarkably specific for the precursors of IL-1␤ and IL-18 by making a...

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TNF induces caspase-dependent inflammation in renal endothelial cells through a Rho- and myosin light chain kinase-dependent mechanism

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