Title

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

Authors

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

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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

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