Impaired IL-18 processing protects caspase-1–deficient mice from ischemic acute renal failure
Vyacheslav Y. Melnikov, … , Robert W. Schrier, Charles L. Edelstein
Vyacheslav Y. Melnikov, … , Robert W. Schrier, Charles L. Edelstein
Published May 1, 2001
Citation Information: J Clin Invest. 2001;107(9):1145-1152. https://doi.org/10.1172/JCI12089.
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Article

Impaired IL-18 processing protects caspase-1–deficient mice from ischemic acute renal failure

Abstract

We sought to determine whether mice deficient in the proinflammatory caspase-1, which cleaves precursors of IL-1β and IL-18, were protected against ischemic acute renal failure (ARF). Caspase-1–/– mice developed less ischemic ARF as judged by renal function and renal histology. These animals had significantly reduced blood urea nitrogen and serum creatinine levels and a lower morphological tubular necrosis score than did wild-type mice with ischemic ARF. Since caspase-1 activates IL-18, lack of mature IL-18 might protect these caspase-1–/– mice from ARF. In wild-type animals, we found that ARF causes kidney IL-18 levels to more than double and induces the conversion of the IL-18 precursor to the mature form. This conversion is not observed in caspase-1–/– ARF mice or sham-operated controls. We then injected wild-type mice with IL-18–neutralizing antiserum before the ischemic insult and found a similar degree of protection from ARF as seen in caspase-1–/– mice. In addition, we observed a fivefold increase in myeloperoxidase activity in control mice with ARF, but no such increase in caspase-1–/– or IL-18 antiserum–treated mice. Finally, we confirmed histologically that caspase-1–/– mice show decreased neutrophil infiltration, indicating that the deleterious role of IL-18 in ischemic ARF may be due to increased neutrophil infiltration.

Authors

Vyacheslav Y. Melnikov, Tevfik Ecder, Giamila Fantuzzi, Britta Siegmund, M. Scott Lucia, Charles A. Dinarello, Robert W. Schrier, Charles L. Edelstein

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Figure 5

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The increase in MPO activity during ischemic ARF is blocked in caspase-1...
The increase in MPO activity during ischemic ARF is blocked in caspase-1–/– mice (a) and in mice treated with anti–IL-18 antiserum (b). In wild-type mice with ischemic ARF (WT ARF), there was an increase in MPO activity compared with sham-operated controls. In caspase-1–/– mice with ischemic ARF, MPO activity was normalized. AP < 0.001 vs. sham; BP < 0.01 vs. WT ARF; and NS vs. sham; n = 6 (a). In separate experiments, in wild-type mice treated with anti–IL-18 antiserum before ischemic ARF (AS ARF), MPO activity was normalized compared with vehicle-treated (Veh) animals. AP < 0.001 vs. sham; BP < 0.01 vs. Veh ARF; and NS vs. sham; n = 6 (b).