Function of Omi/HtrA2 in Renal Tubular Cell Death

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DESCRIPTION (provided by applicant): Acute renal failure (ARF) is a serious medical problem that occurs in 5% of all hospitalized patients. The prognosis of ARF is poor and has remained unchanged over the past three decades carrying a high mortality rate of about 50%. Although ARF is the result of many causes, the most common cause is injury to the renal tubular epithelial cells (RTEC). These cells, once injured, die by necrosis or apoptosis depending on the nature and severity of the insult. Severe injury usually triggers necrosis whereas milder insults to the kidney cause apoptotic death of the RTEC. Necrosis is difficult to prevent, whereas apoptosis can potentially be modulated to maintain cell viability. Therefore, identifying the different components of the apoptotic pathway, especially the ones that play a major role in kidney, can help us understand renal injury-induced apoptosis. These new components can also provide specific and novel targets for intervention to help patients with acute renal failure. Our studies are focused on a recently isolated and characterized pro-apoptotic protease Omi, also known as HtrA2, and its role in renal injury. This protein is present in the mitochondria and is released to the cytoplasm upon induction of apoptosis. In this capacity, Omi is unique both in its structure as well as its function. In the cytoplasm, Omi can induce apoptosis through a caspase-dependent as well as in a caspase-independent pathway. It is the aim of this proposal to investigate the potential role of Omi in the apoptotic cell death that occurs in RTEC. Our studies will investigate the involvement of Omi in renal injury and the molecular events that follow its activation leading to apoptosis. Furthermore, by blocking the proteolytic activity of Omi using a specific inhibitor, a new approach to potentially protect and maintain cell viability will be tested.