Post-irradiation intervention to mitigate and treat chronic renal injuries

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This project is based on the hypothesis that renal injury will occur after certain types of radiological terrorism events, and that this injury can be both mitigated and treated. We are using the convention adopted by recent NCI workshops that: "mitigation" refers to therapies that are effective when begun after irradiation, but before there is pathophysiological evidence of radiation injury; and "treatment" refers to therapies which are effective when begun after pathophysiological evidence of radiation injury is present. We have used a rat total body irradiation (TBI) model to demonstrate that angiotensin converting enzyme (ACE) inhibitors and angiotensin II (All) type-1 receptor antagonists (AT1 blockers) are effective for the mitigation and treatment of radiation-induced renal injury. Our previous studies have used the types of fractionated high-dose-rate radiation schedules that are used in radiation oncology and bone marrow transplantation (BMT), have been oriented towards understanding the pathophysiological basis of the injury, and have often used agents that are not yet approved for human use. The proposed studies will use the types of radiation schedules most likely to present in radiological terrorism events (single doses at high or low dose rates) and will focus on developing products suitable for clinical use. The specific aims of this proposal are to: demonstrate that captopril (an FDA-approved ACE inhibitor) and losartan (an FDA-approved AT1 blocker) can be used to both mitigate and treat the radiation-induced renal injuries that could arise from radiological terrorism; determine whether these agents are acting via suppression of chronic oxidative stress; and determine whether an in vitro glomerular leakage assay can be used as a high through-put screening tool for finding new mitigators of radiation-induced renal injury. In summary, experimental studies suggest radiation-induced renal injury can be treated. The goal of this project is to bring one or more of these experimental approaches into clinical practice.