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

J Clin Invest. 2002 Oct;110(8):1083-91. doi: 10.1172/JCI15623.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

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
  • Interleukin-18 / metabolism*
  • Kidney / immunology
  • Kidney / pathology
  • Kidney / physiopathology
  • Kidney Tubular Necrosis, Acute / pathology
  • Kidney Tubular Necrosis, Acute / physiopathology*
  • Kidney Tubular Necrosis, Acute / prevention & control
  • Kidney Tubules, Proximal / immunology
  • Lymphocyte Depletion
  • Mice
  • Mice, Inbred C57BL
  • Neutrophils / drug effects
  • Neutrophils / pathology
  • Neutrophils / physiology*
  • Quinolines / pharmacology


  • 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