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

¹Department of Medicine, Divisions of Renal Diseases and Hypertension and Infectious Diseases, University of Colorado Health Sciences Center, Denver, Colorado; and ²Department of Pathology, University Hospital Dubrava, Zagreb, Croatia

Submitted 12 April 2004 ; accepted in final form 30 December 2004

Caspase-1-deficient (–/–) 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 LPS-treated mice, the glomerular filtration rate (GFR) was significantly higher in caspase-1 –/– 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 antiserum-treated) 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 –/– mice with endotoxemic ARF. In LPS- vs. vehicle-treated wild-type mice, renal IL-1 was significantly increased. In both LPS- and vehicle-treated caspase-1 –/– mice, renal IL-1 was very low. In summary, caspase-1 –/– 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

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