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A Reproducible Intensive Care Unit-Oriented Endotoxin Model in Rats
Published on: February 20, 2021
Acute renal failure in endotoxemia is dependent on caspase activation
Rongqing Guo1, Ying Wang, Andrew W Minto
1Section of Nephrology, University of Chicago, MC5100, Room S511, 5841 South Maryland Avenue, Chicago, IL 60637, USA.
Abstract:
In previous work, it was demonstrated that apoptosis occurs in the kidney during LPS-induced acute renal failure (ARF). However, the relative importance of apoptosis in LPS-induced ARF remained unproven. Because the caspase enzyme cascade is responsible for carrying out apoptosis, it was hypothesized that treatment with a caspase inhibitor would protect mice from LPS-induced ARF. C57BL/6 mice received an injection of LPS and were treated with either the broad-spectrum caspase inhibitor z-VAD-fmk or vehicle and compared with unmanipulated mice. LPS induced a significant increase in caspase-3 activity in vehicle-treated mice, which was significantly inhibited by z-VAD. Mice that were treated with z-VAD were protected from ARF and demonstrated significantly less apoptosis as measured by both terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining and DNA laddering. Although apoptosis is classically described as a noninflammatory process, z-VAD treatment significantly attenuated multiple markers of inflammation, such as renal neutrophil infiltration and renal expression of the neutrophil chemotactic factor macrophage inflammatory protein-2. Thus, caspase inhibition may protect against LPS-induced ARF not only by preventing apoptotic cell death but also by inhibiting inflammation. These data raise the possibility that apoptotic kidney cells may actually be a source of this local inflammation, contributing to subsequent nonapoptotic renal injury.
Insights
Caspase inhibition protects against acute renal failure (ARF) by reducing kidney cell apoptosis and inflammation. This suggests targeting caspases may be a novel therapeutic strategy for ARF.
Area of Science:
- Nephrology
- Cell Biology
- Immunology
Background:
- Apoptosis (programmed cell death) is known to occur in the kidney during lipopolysaccharide (LPS)-induced acute renal failure (ARF).
- The precise role and significance of apoptosis in the pathogenesis of LPS-induced ARF were not fully established.
- The caspase enzyme cascade is a critical executioner of apoptosis.
Purpose of the Study:
- To investigate the protective effect of a broad-spectrum caspase inhibitor against LPS-induced ARF in mice.
- To determine if caspase inhibition reduces apoptosis and inflammation in the kidney during LPS-induced ARF.
Main Methods:
- C57BL/6 mice were injected with LPS and treated with either the caspase inhibitor z-VAD-fmk or a vehicle control.
- Assessed renal function, caspase-3 activity, apoptosis (TUNL staining, DNA laddering), and inflammatory markers (neutrophil infiltration, MIP-2 expression).
Main Results:
- LPS significantly increased caspase-3 activity, which was inhibited by z-VAD-fmk.
- z-VAD-fmk treatment protected mice from ARF, significantly reducing apoptosis.
- Caspase inhibition also attenuated renal neutrophil infiltration and macrophage inflammatory protein-2 expression, indicating reduced inflammation.
Conclusions:
- Caspase inhibition protects against LPS-induced ARF by mitigating both apoptotic cell death and renal inflammation.
- These findings suggest that apoptotic kidney cells might contribute to inflammation and subsequent injury in ARF.
- Targeting caspases presents a potential therapeutic avenue for managing LPS-induced ARF.
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