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

Citation
Vy. Melnikov et al., Impaired IL-18 processing protects caspase-1-deficient mice from ischemic acute renal failure, J CLIN INV, 107(9), 2001, pp. 1145-1152
Citations number
31
Categorie Soggetti
Medical Research General Topics
Journal title
JOURNAL OF CLINICAL INVESTIGATION
ISSN journal
00219738 → ACNP
Volume
107
Issue
9
Year of publication
2001
Pages
1145 - 1152
Database
ISI
SICI code
0021-9738(200105)107:9<1145:IIPPCM>2.0.ZU;2-X
Abstract
We sought to determine whether mice deficient in the proinflammatory caspas e-1, which cleaves precursors of IL-1 beta and IL-18, were protected agains t ischemic acute renal failure (ARF). Caspase-1(-/-) mice developed less is chemic ARF as judged by renal function and renal histology. These animals h ad significantly reduced blood urea nitrogen and serum creatinine levels an d 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 con version of the IL-18 precursor to the mature form. This conversion is not o bserved in caspase-1(-/-) ARF mice or sham-operated controls. We then injec ted wild-type mice with IL-18-neutralizing antiserum before the ischemic in sult 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 neut rophil infiltration.