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.
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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