title: Endotoxemic acute renal failure is attenuated in caspase-1-deficient mice.
abstract: 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-1beta and IL-18 were investigated. IL-1beta 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-1alpha was significantly increased. In both LPS- and vehicle-treated caspase-1 -/- mice, renal IL-1alpha was very low. In summary, caspase-1 -/- mice are functionally protected against endotoxemic ARF. Neutralization of IL-1beta and IL-18 is not functionally protective. The role of the intracellular proinflammatory cytokine IL-1alpha in endotoxemic ARF merits further study.
authors.affiliation: Department of Medicine, Division of Renal Diseases, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Sarah
authors.initials: S
authors.lastname: Faubel
authors.forename: Danica
authors.initials: D
authors.lastname: Ljubanovic
authors.forename: Amit
authors.initials: A
authors.lastname: Mitra
authors.forename: Sandor A
authors.initials: SA
authors.lastname: Falk
authors.forename: Jun
authors.initials: J
authors.lastname: Kim
authors.forename: Yunxia
authors.initials: Y
authors.lastname: Tao
authors.forename: Andrei
authors.initials: A
authors.lastname: Soloviev
authors.forename: Leonid L
authors.initials: LL
authors.lastname: Reznikov
authors.forename: Charles A
authors.initials: CA
authors.lastname: Dinarello
authors.forename: Robert W
authors.initials: RW
authors.lastname: Schrier
authors.forename: Charles L
authors.initials: CL
authors.lastname: Edelstein
mesh_terms: D058186:Acute Kidney Injury / Q000276:immunology / Q000473:pathology / Q000503:physiopathology*; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D002154:Calpain / Q000378:metabolism; D020170:Caspase 1 / Q000235:genetics* / Q000378:metabolism; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D019446:Endotoxemia / Q000276:immunology / Q000473:pathology / Q000503:physiopathology*; D005919:Glomerular Filtration Rate; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000378:metabolism; D020382:Interleukin-18 / Q000276:immunology / Q000378:metabolism; D007668:Kidney / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009195:Peroxidase / Q000378:metabolism; D012795:Sialoglycoproteins / Q000276:immunology / Q000378:metabolism
chemical_list: D000906:Antibodies; C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D020382:Interleukin-18; D012795:Sialoglycoproteins; D009195:Peroxidase; D002154:Calpain; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D020170:Caspase 1