IntroductionIn the kidney, activation of caspases has been described during hypoxic proximal tubular necrotic injury in vitro and pan-caspase inhibition protects against this injury (1, 2). A recent study demonstrates that a pan-caspase inhibitor protects against ischemic ARF in mice by inhibition of distal tubule apoptosis and subsequent inflammation (3). In this study, however, the effect of caspase inhibition on the development of ischemic acute tubular necrosis (ATN), a well-established mechanism of tubular injury, was not studied. Also, in these studies, the use of pan-caspase inhibitors makes it difficult to implicate a specific caspase in hypoxic/ischemic injury. Thus, the mechanism of caspase-mediated ischemic ARF and the specific caspase involved in this renal ischemia-reperfusion injury is not clear.The caspases are a family of intracellular cysteine proteases. Caspases participate in two distinct signaling pathways: (a) activation of proinflammatory cytokines and (b) promotion of apoptotic cell death (4). Caspase-1 (previously known as IL-1β-converting enzyme or ICE) plays a major role in the cleavage of the IL-1β precursor and the IL-18 precursor. Caspase-1 is remarkably specific for these precursors of IL-1β and IL-18 (IFN-γ-inducing factor) by making a single initial cut in each procytokine, which results in an active mature cytokine secreted into the extracellular space (5, 6). Although thymocytes from caspase-1 -/-mice were found to be resistant to apoptosis induced by Fas Ab (7), subsequent studies did not demonstrate a role of caspase-1 in apoptosis (8).To establish a pathogenic role of caspase-1 in cell injury, caspase-1 -/-mice have been used. These caspase-1 -/-mice have a defect in production of mature IL-1β and IL-18 and are protected against lethal endotoxemia (7,8). The fact that IL-1β -/-mice are not protected against endotoxemia (9) suggests a potential role of IL-18 in the lethal outcome during sepsis. Moreover, in ischemic ARF, IL-1 receptor-knockout mice or mice treated with IL-1-receptor antagonist (IL-1Ra) are not protected against ischemic ARF (10). Taken together, therefore, these previous studies suggest that IL-18 may be a potential mediator of ischemic ARF. Thus, any protective effect against renal ischemia-reperfusion injury in caspase -/-mice may be due to a failure of this caspase to activate IL-18.In the present study, we used caspase-1 -/-mice to test the hypothesis that caspase-1 is a mediator of ischemic ARF in mice. The fact that expression of the proinflammatory cytokines IL-1β and IL-18 is altered in caspase-1 -/-mice makes these mice a very suitable model for further studying the mechanism of ischemic ARF. Thus, the aims of the present study were to determine whether caspase-1 -/-mice are protected against ischemic ARF and to explore the mechanisms of this protection, particularly the role of IL-18. 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...

No abstract

These results demonstrate a role of TNF in the early renal dysfunction (16 h) in a septic mouse model independent of iNOS, hypotension, apoptosis, leukocyte accumulation, and morphological alterations, thus suggesting renal hypoperfusion secondary to an imbalance between, as yet to be defined, renal vasoconstrictors and vasodilators.

IntroductionThe caspases are a family of intracellular cysteine proteases. Caspases participate in two distinct signaling pathways: (a) activation of proinflammatory cytokines by caspase-1 (previously known as IL-1β-converting enzyme, or ICE), and (b) promotion of apoptotic cell death via caspase-3. There is now considerable evidence that caspases are also involved in necrotic cell death in vitro. Inhibition of caspases protects against necrotic cell death induced by hypoxia in renal tubules in culture (1) and freshly isolated rat proximal tubules (2). In rat kidneys with acute tubular necrosis (ATN), both caspase-1 and caspase-3 mRNA and protein expression (3) as well as caspase-3 activity (4) are increased. Caspase inhibition attenuates distal tubule apoptosis and inflammation in ischemic acute renal failure (ARF) in mice (5). However, the effect of caspase inhibitors on ATN, the predominant pathological process in animal models of ischemic ARF and in posttransplant ARF in humans, is not known. Thus, on the background of caspase inhibitor studies in vitro in proximal tubules and in vivo studies in kidney, we determined the effect of the newly developed caspase inhibitor Quinoline-Val-Asp(Ome)-CH 2 -OPH (OPH-001) on the functional and morphological changes in ischemic ARF in mice. While the use of caspase-deficient mice has provided extensive information about the role of individual caspases in disease processes, the study of caspase inhibitors in vivo represents an important initial step toward possible therapeutic effects of caspase inhibition.The proinflammatory caspase-1 plays a major role in the cleavage of the IL-1β precursor and the IL-18 precursor. Caspase-1 is remarkably specific for the precursors of IL-1β and IL-18 (IFN-γ-inducing factor) by making a single initial cut in each procytokine, which results in an active mature cytokine secreted into the extracellular space (6). We have demonstrated that caspase-1-deficient mice are functionally and histologically protected against ischemic ARF and that this protection is associated with decreased conversion of IL-18 precursor to the mature form in the kidney (7). In this study, the administration of IL-18-neutralizing antiserum protected against ischemic ARF, confirming the deleterious role of IL-18 in the Having recently described the injurious role of caspase-1-mediated production of the proinflammatory cytokine IL-18 in ischemic acute renal failure (ARF), we report here on the effect of the newly developed caspase inhibitor Quinoline-Val-Asp(Ome)-CH 2 -OPH (OPH-001) on caspase-1, IL-18, neutrophil infiltration, and renal function in ischemic ARF. C57BL/6 mice with ischemic ARF treated with OPH-001 had a marked (100%) reduction in blood urea nitrogen (BUN) and serum creatinine and a highly significant reduction in morphological acute tubular necrosis (ATN) score compared with vehicle-treated mice. OPH-001 significantly reduced the increase in caspase-1 activity and IL-18 and prevented neutrophil infiltration in the kidney during ischemic ARF. To evalua...

IntroductionThe caspases are a family of intracellular cysteine proteases. Caspases participate in two distinct signaling pathways: (a) activation of proinflammatory cytokines by caspase-1 (previously known as IL-1β-converting enzyme, or ICE), and (b) promotion of apoptotic cell death via caspase-3. There is now considerable evidence that caspases are also involved in necrotic cell death in vitro. Inhibition of caspases protects against necrotic cell death induced by hypoxia in renal tubules in culture (1) and freshly isolated rat proximal tubules (2). In rat kidneys with acute tubular necrosis (ATN), both caspase-1 and caspase-3 mRNA and protein expression (3) as well as caspase-3 activity (4) are increased. Caspase inhibition attenuates distal tubule apoptosis and inflammation in ischemic acute renal failure (ARF) in mice (5). However, the effect of caspase inhibitors on ATN, the predominant pathological process in animal models of ischemic ARF and in posttransplant ARF in humans, is not known. Thus, on the background of caspase inhibitor studies in vitro in proximal tubules and in vivo studies in kidney, we determined the effect of the newly developed caspase inhibitor Quinoline-Val-Asp(Ome)-CH 2 -OPH (OPH-001) on the functional and morphological changes in ischemic ARF in mice. While the use of caspase-deficient mice has provided extensive information about the role of individual caspases in disease processes, the study of caspase inhibitors in vivo represents an important initial step toward possible therapeutic effects of caspase inhibition.The proinflammatory caspase-1 plays a major role in the cleavage of the IL-1β precursor and the IL-18 precursor. Caspase-1 is remarkably specific for the precursors of IL-1β and IL-18 (IFN-γ-inducing factor) by making a single initial cut in each procytokine, which results in an active mature cytokine secreted into the extracellular space (6). We have demonstrated that caspase-1-deficient mice are functionally and histologically protected against ischemic ARF and that this protection is associated with decreased conversion of IL-18 precursor to the mature form in the kidney (7). In this study, the administration of IL-18-neutralizing antiserum protected against ischemic ARF, confirming the deleterious role of IL-18 in the Having recently described the injurious role of caspase-1-mediated production of the proinflammatory cytokine IL-18 in ischemic acute renal failure (ARF), we report here on the effect of the newly developed caspase inhibitor Quinoline-Val-Asp(Ome)-CH 2 -OPH (OPH-001) on caspase-1, IL-18, neutrophil infiltration, and renal function in ischemic ARF. C57BL/6 mice with ischemic ARF treated with OPH-001 had a marked (100%) reduction in blood urea nitrogen (BUN) and serum creatinine and a highly significant reduction in morphological acute tubular necrosis (ATN) score compared with vehicle-treated mice. OPH-001 significantly reduced the increase in caspase-1 activity and IL-18 and prevented neutrophil infiltration in the kidney during ischemic ARF. To evalua...