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1 Biomolecular Science Center, Burnett College of Biomedical Science, University of Central Florida, Orlando, FL, USA
2 Renal Division, Brigham and Women's Hospital/Harvard Medical School, Boston, MA, USA
3 Department of Microbiology and Immunology, Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, PA, USA
* To whom correspondence should be addressed. E-mail: azervos{at}mail.ucf.edu.
Omi/HtrA2 is a mitochondrial pro-apoptotic serine protease that is able to induce both caspase-dependent and caspase-independent cell death. Following apoptotic stimuli, Omi is released to the cytoplasm, where it binds and cleaves inhibitor of apoptosis proteins (IAPs). In this report we investigated the role of Omi in renal cell death following cisplatin treatment. Using primary mouse proximal tubule (MPT) cells, as well as established renal cell lines, we show that the level of Omi protein is up-regulated after treatment with cisplatin. This up-regulation 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.
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