Omi/HtrA2 protease mediates cisplatin-induced cell death in renal cells

    Authors

    L. Cilenti; G. A. Kyriazis; M. M. Soundarapandian; V. Stratico; A. Yerkes; K. M. Park; A. M. Sheridan; E. S. Alnemri; J. V. Bonventre;A. S. Zervos

    Comments

    Authors: contact us about adding a copy of your work at STARS@ucf.edu

    Abbreviated Journal Title

    Am. J. Physiol.-Renal Physiol.

    Keywords

    serine protease; ucf-101; apoptosis; mitochondrial protein; proximal; tubular cells; PROXIMAL TUBULAR CELLS; SERINE-PROTEASE; APOPTOSIS PROTEINS; CASPASE; ACTIVITY; HEYMANN NEPHRITIS; KIDNEY ISCHEMIA; HTRA FAMILY; INHIBITOR; NECROSIS; INJURY; Physiology; Urology & Nephrology

    Abstract

    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.

    Journal Title

    American Journal of Physiology-Renal Physiology

    Volume

    288

    Issue/Number

    2

    Publication Date

    1-1-2005

    Document Type

    Article

    Language

    English

    First Page

    F371

    Last Page

    F379

    WOS Identifier

    WOS:000226147900016

    ISSN

    1931-857X

    Share

    COinS