Caspase-7, Fas and FasL in Long-Term Renal Ischaemia/Reperfusion and Immunosuppressive Injuries in Rats

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Abstract

Background/Aims: Ischaemia/reperfusion (I/R) injury is important in kidney transplantation. We have previously demonstrated that long-term I/R injury and immunosuppression affect apoptosis and inflammation, but the underlying mechanisms are far from clear. In this study, the involvement of caspase-7, Fas and FasL was further investigated. Methods: The right renal pedicle was clamped for 45 min followed by left nephrectomy in 40 rats. Cyclosporine (CsA), tacrolimus (Tac), rapamycin (Rap) or mycophenolate mofetil (MMF) were administered daily for 16 weeks. Caspase-7, Fas and FasL expression, and their correlations with caspase-3, apoptosis, inflammation, renal structure and function were evaluated. Results: Active caspase-7 was significantly increased in I/R and CsA-treated kidneys and decreased by Tac, Rap and MMF, while the caspase-7 precursor was enhanced by Rap. Active caspase-7-stained cells were scattered throughout the tubulointerstitium and often had apoptotic features. Fas, but not FasL, was increased in I/R and CsA-treated kidneys and decreased by Rap and MMF. Fas and FasL proteins were mainly located in dilated tubules. There were close correlations among caspase-7, Fas, caspase-3, apoptosis, inflammation, renal structure and function. Conclusion: Caspase-7, associated with caspase-3, apoptosis and inflammation, might be involved in long-term I/R and immunosuppressive injury, at least in part through the Fas-signalling pathway.

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Most cited references 27

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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.

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MCF-7 human breast cancer cells do not express caspase 3, thought by some to be a critical component of the apoptosis cascade. Nonetheless, both mock- and bcl-2-transfected MCF-7 cells undergo apoptosis after treatment with a variety of stimuli, including the DNA-cleaving antimitotic agent, neocarzinostatin (NCS). Transfection with bcl-2 shifts the concentration-response curve to NCS but does not change the phenomenology of apoptosis when it occurs. In both cases, NCS treatment results in condensation and fragmentation of MCF-7 cell nuclei and release of cytochrome c from the mitochondria to the cytosol. This apoptosis is accompanied by decreased levels of Bcl-2 and increased levels of Bax. Using a series of caspase inhibitors with overlapping specificities, enzyme-specific chromogenic substrates, and an antibody specific for activated caspase 7, we have determined that apoptosis in MCF-7 cells proceeds via sequential activation of caspases 9, 7 and 6. P21 is detected only after activation of caspase 7, and P53 is neither expressed at baseline nor up-regulated with apoptosis induction. This pathway bypasses the need for activated caspase 3 in these cells.

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Caspase-3 is a major cell death effector protease in the adult and neonatal nervous system. We found a greater number and higher density of cells in the cortex of caspase-3(-/-) adult mice, consistent with a defect in developmental cell death. Caspase-3(-/-) mice were also more resistant to ischemic stress both in vivo and in vitro. After 2 h of ischemia and 48 h of reperfusion, cortical infarct volume was reduced by 55%, and the density of terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling-positive cells was decreased by 36% compared with wild type. When subjected to oxygen-glucose deprivation (2 h), cortical neurons cultured from mice deficient in caspase-3 expression were also more resistant to cell death by 59%. Mutant brains showed caspase-specific poly(ADP-ribose) polymerase cleavage product (85-kDa fragment) in vivo and in vitro, suggesting redundant mechanisms and persistence of caspase-mediated cell death. In the present study, we found that caspase-8 mediated poly(ADP-ribose) polymerase cleavage in caspase-3(-/-) neurons in vivo and in vitro. In addition, mutant neurons showed no evidence of compensatory activation by caspase-6 or caspase-7 after ischemia. Taken together, these data extend the pharmacological evidence supporting an important role for caspase-3 and caspase-8 as cell death mediators in mammalian cortex and indicate the potential advantages of targeting more than a single caspase family member to treat ischemic cell injury.

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Author and article information

Journal

Journal ID (publisher-id): AJN

Journal ID (nlm-ta): Am J Nephrol

Journal ID (doi): 10.1159/issn.0250-8095

Title: American Journal of Nephrology

Publisher: S. Karger AG

ISSN (Print): 0250-8095

ISSN (Electronic): 1421-9670

Publication date Subscription-year: 2007

Publication date (Print): July 2007

Publication date (Electronic): 26 June 2007

Volume: 27

Issue: 4

Pages: 397-408

Affiliations

^aDepartment of Infection, Immunity and Inflammation, ^bDepartment of Cancer Studies and Molecular Medicine and ^cDepartment of Cardiovascular Sciences, University of Leicester, Leicester, UK

Article

Publisher ID: 104741 Other ID: Am J Nephrol 2007;27:397–408

DOI: 10.1159/000104741

PubMed ID: 17596683

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