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NDT Advance Access originally published online on January 25, 2007
Nephrology Dialysis Transplantation 2007 22(4):1052-1061; doi:10.1093/ndt/gfl775
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© The Author [2007]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Proximal tubules from caspase-1-deficient mice are protected against hypoxia-induced membrane injury

Charles L. Edelstein1, Thomas S. Hoke1, Hilary Somerset1, Wenfeng Fang2, Christina L. Klein1, Charles A. Dinarello1 and Sarah Faubel1

1University of Colorado Health Science Center, Department of Internal Medicine, Denver Colorado, USA and 2Division of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital - Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan

Correspondence and offprint requests to: Sarah Faubel, MD, Biomedical Research Building, Room 512A 4200 East 9th Ave, Box C281 Denver CO, 80262 Email sarah.faubel{at}uchsc.edu



  Abstract

Background. Caspase-1 is a proinflammatory caspase via activation of the cytokine IL-18. We have recently demonstrated that the caspase-1-mediated production of IL-18 plays a deleterious role in ischaemic acute renal failure (ARF) which is independent of neutrophils and CD4+ T cells. The role of caspase-1 in hypoxia-induced membrane injury of proximal tubules (PT) in vitro is unknown.

Methods. Freshly isolated mouse PT exposed to 25 min of hypoxia were used to study the role of caspases, caspase-1 and IL-18 in hypoxia-induced membrane injury. Lactate dehydrogenase (LDH) release into the PT medium was used as a biochemical parameter of cell membrane damage. IL-18 was determined by enzyme-linked immunosorbent assay (ELISA) and immunoblotting.

Results. PT pre-incubated with the novel pancaspase inhibitor IDN-8050 were protected; LDH release (%) was 35 ± 3 in vehicle-treated hypoxic PT and 21 ± 2 in IDN-8050-treated hypoxic PT (P < 0.01, n = 6). To investigate the mechanism of protection and examine the role of caspase-1 specifically, PT were isolated in parallel from wild-type and caspase-1- deficient (–/–) mice. PT from caspase-1 –/– mice demonstrated less hypoxia-induced membrane injury. LDH release was 37 ± 2 in wild-type hypoxic PT and 28 ± 2 in caspase-1 –/– hypoxic PT (P < 0.01, n = 12). IL-18 was detected in PT by immunoblotting and ELISA. PT pre-incubated with IL-18 binding protein, an inhibitor of IL-18, were not protected.

Conclusions. These studies demonstrate a deleterious effect of the proinflammatory caspase, caspase-1, on PT in vitro in the absence of inflammatory cells and vascular effects.

Keywords: apoptosis; caspase; tubular cells; renal hypoxia

Received for publication: 10.12.05
Accepted in revised form: 29.11.06


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