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PMID: 12393844 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Neutrophil-independent mechanisms of caspase-1- and IL-18-mediated ischemic acute tubular necrosis in mice.

The Journal of clinical investigation ·Vol. 110 ·No. 8 ·2002-10-00 ·Pages 1083-91

Melnikov VY, Faubel S, Siegmund B, Lucia MS, Ljubanovic D, Edelstein CL

Abstract

Having recently described the injurious role of caspase-1-mediated production of the proinflammatory cytokine IL-18 in ischemic acute renal failure (ARF), we report here on the effect of the newly developed caspase inhibitor Quinoline-Val-Asp(Ome)-CH(2)-OPH (OPH-001) on caspase-1, IL-18, neutrophil infiltration, and renal function in ischemic ARF. C57BL/6 mice with ischemic ARF treated with OPH-001 had a marked (100%) reduction in blood urea nitrogen (BUN) and serum creatinine and a highly significant reduction in morphological acute tubular necrosis (ATN) score compared with vehicle-treated mice. OPH-001 significantly reduced the increase in caspase-1 activity and IL-18 and prevented neutrophil infiltration in the kidney during ischemic ARF. To evaluate whether this lack of neutrophil infiltration was contributing to the protection against ischemic ARF, a model of neutrophil depletion was developed. Neutrophil-depleted mice had a small (18%) reduction in serum creatinine during ischemic ARF but no reduction in ATN score despite a lack of neutrophil infiltration in the kidney. Remarkably, caspase-1 activity and IL-18 were significantly increased in the kidney in neutrophil-depleted mice with ARF. In addition, IL-18 antiserum-treated neutrophil-depleted mice with ischemic ARF had a significant (75%) reduction in serum creatinine and a significant reduction in ATN score compared with vehicle-treated neutrophil-depleted mice. These results suggest a novel neutrophil-independent mechanism of IL-18-mediated ischemic ARF.

MeSH Terms
Amino Acid Chloromethyl Ketones/pharmacology Animals Antibodies/administration & dosage Caspase 1/metabolism Caspase 3 Caspase Inhibitors Creatinine/blood Cysteine Proteinase Inhibitors/pharmacology Disease Models, Animal Inflammation Mediators/metabolism Interleukin-18/antagonists & inhibitors,metabolism Kidney/immunology,pathology,physiopathology Kidney Tubular Necrosis, Acute/pathology,physiopathology,prevention & control Kidney Tubules, Proximal/immunology Lymphocyte Depletion Mice Mice, Inbred C57BL Neutrophils/drug effects,pathology,physiology Quinolines/pharmacology
Chemicals
Amino Acid Chloromethyl Ketones Antibodies Caspase Inhibitors Cysteine Proteinase Inhibitors Inflammation Mediators Interleukin-18 Quinolines quinoline-val-asp(OMe)-CH2-OPH Creatinine Casp3 protein, mouse Caspase 3 Caspase 1
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Melnikov Vyacheslav Y
Department of Medicine, University of Colorado School of Medicine, 4200 East 9th Avenue, Denver, Colorado 80262, USA.
Faubel Sarah
Siegmund Britta
Lucia M Scott
Ljubanovic Danica
Edelstein Charles L
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Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
0021-9738
DOI
10.1172/JCI15623
Published
2002-10-00
Pages
1083-91
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC150794
Subset
IM
Grants
NIDDK NIH HHS · R01 DK056851 · United States
NIDDK NIH HHS · 1R01 DK 56851 · United States
External Links
PubMed source DOI: 10.1172/JCI15623 PMC Full Text View journal details
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