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Am J Physiol Renal Physiol (January 11, 2005). doi:10.1152/ajprenal.00130.2004
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Submitted on April 12, 2004
Accepted on December 30, 2004

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

Wei Wang1, Sarah Faubel1, Danica Ljubanovic2, Amit Mitra1, Jun Kim1, Yunxia Tao1, Andrei Soloviev1, Leonid L. Reznikov1, Charles A. Dinarello1, Robert W. Schrier1*, and Charles L. Edelstein1

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

* To whom correspondence should be addressed. E-mail: robert.schrier{at}uchsc.edu.

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 non hypotensive model of endotoxemic ARF. Mice were injected with lipopolysaccharide (LPS) 2.5 mg IP that induces endotoxemic ARF. On immunoblot analysis of whole kidney there was an increase in caspase-1 protein in LPS-treated mice compared to vehicle treated controls. In LPS treated mice, glomerular filtration rate (GFR) was significantly higher in caspase-1 -/- vs. wild type mice at 16 and 36 hours after LPS. To determine the mechanism of this protection, the caspase-1-activated cytokines IL-1{beta} and IL-18 were investigated. IL-1{beta} 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 to control mice. In addition, tubular cell apoptosis, neutrophil infiltration, myeloperoxidase (MPO) 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{alpha} was significantly increased. In both LPS and vehicle treated caspase-1 -/- mice, renal IL-1{alpha} was very low. In summary, caspase-1 -/- mice are functionally protected against endotoxemic ARF. Neutralization of IL-1{beta} and IL-18 is not functionally protective. The role of the intracellular pro-inflammatory cytokine, IL-1{alpha}, in endotoxemic ARF merits further study.




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