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1Biomolecular Science Center, Burnett College of Biomedical Science, University of Central Florida, Orlando, Florida; 3Center of Apoptosis Research and Department of Microbiology and Immunology, Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, Pennsylvania; and 2Renal Division, Brigham and Women's Hospital/Harvard Medical School, Boston, Massachusetts
Submitted 30 April 2004 ; accepted in final form 27 September 2004
Omi/HtrA2 is a mitochondrial proapoptotic serine protease that is able to induce both caspase-dependent and caspase-independent cell death. After apoptotic stimuli, Omi is released to the cytoplasm where it binds and cleaves inhibitor of apoptosis proteins. In this report, we investigated the role of Omi in renal cell death following cisplatin treatment. Using primary mouse proximal tubule cells, as well as established renal cell lines, we show that the level of Omi protein is upregulated after treatment with cisplatin. This upregulation is followed by the release of Omi from mitochondria to the cytoplasm and degradation of XIAP. Reducing the endogenous level of Omi protein using RNA interference renders renal cells resistant to cisplatin-induced cell death. Furthermore, we show that the proteolytic activity of Omi is necessary and essential for cisplatin-induced cell death in this system. When renal cells are treated with Omi's specific inhibitor, ucf-101, they become significantly resistant to cisplatin-induced cell death. Ucf-101 was also able to minimize cisplatin-induced nephrotoxic injury in animals. Our results demonstrate that Omi is a major mediator of cisplatin-induced cell death in renal cells and suggest a way to limit renal injury by specifically inhibiting its proteolytic activity.
serine protease; ucf-101; apoptosis; mitochondrial protein; proximal tubular cells
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