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Updated: Aug 2, 2026
Ischemia-reperfusion Model of Acute Kidney Injury and Post Injury Fibrosis in Mice
Published on: August 9, 2013
Impaired IL-18 processing protects caspase-1-deficient mice from ischemic acute renal failure
V Y Melnikov1, T Ecder, G Fantuzzi
1Department of Medicine, University of Colorado School of Medicine, Denver, Colorado 80262, USA.
Abstract:
We sought to determine whether mice deficient in the proinflammatory caspase-1, which cleaves precursors of IL-1 beta 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.
Insights
Mice lacking caspase-1 (a protein that activates IL-18) showed reduced kidney damage from ischemic acute renal failure (ARF). Blocking IL-18 also protected against ARF, suggesting IL-18 contributes to kidney injury.
Area of Science:
- Renal Physiology
- Inflammation Biology
- Molecular Medicine
Background:
- Ischemic acute renal failure (ARF) is a significant clinical challenge.
- The role of inflammatory mediators like caspase-1 and IL-18 in ARF pathogenesis is not fully understood.
Purpose of the Study:
- To investigate the protective effect of caspase-1 deficiency against ischemic ARF in mice.
- To determine the contribution of IL-18 to the development of ischemic ARF.
Main Methods:
- Comparison of renal function and histology in caspase-1 deficient (caspase-1(-/-)) mice versus wild-type mice subjected to ischemic ARF.
- Measurement of blood urea nitrogen (BUN) and serum creatinine levels.
- Assessment of IL-18 precursor to mature form conversion in kidney tissue.
- Administration of IL-18 neutralizing antiserum to wild-type mice prior to ischemic insult.
- Evaluation of myeloperoxidase (MPO) activity and neutrophil infiltration in kidney tissue.
Main Results:
- Caspase-1(-/-) mice exhibited significantly reduced renal dysfunction and histological damage compared to wild-type mice following ischemic ARF.
- ARF induced a marked increase in kidney IL-18 levels and processing of its precursor in wild-type mice, which was absent in caspase-1(-/-) mice.
- Neutralization of IL-18 provided similar protection against ARF as observed in caspase-1(-/-) mice.
- Myeloperoxidase activity and neutrophil infiltration were significantly reduced in both caspase-1(-/-) and IL-18 antiserum-treated mice.
Conclusions:
- Caspase-1 deficiency confers protection against ischemic ARF.
- IL-18 plays a critical role in the development of ischemic ARF, potentially mediated through increased neutrophil infiltration.
- Targeting the caspase-1/IL-18 pathway may represent a therapeutic strategy for preventing or treating ischemic ARF.
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