Kidney Response to Radiation and Chemotherapy

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DESCRIPTION (provided by applicant): This project is based on the hypothesis that late radiation-induced normal tissue injuries can be prevented and/or treated with post-irradiation pharmacologic intervention. The rat radiation nephropathy model is used to study the pathophysiological mechanism(s) of late radiation-induced normal tissue injuries, and these mechanistic understandings are used in the development of methods for prophylaxis and treatment of these injuries. The discovery that radiation nephropathy is a major complication of bone marrow transplantation (BMT) conditioning, and that the rat was an excellent model for this nephropathy, added a preclinical component to the project. The discovery that angiotensin converting enzyme (ACE) inhibitors and an angiotensin II (AII) blockers could be used for the prophylaxis and treatment of BMT nephropathy led directly to clinical studies. The studies are strongly influenced by the finding that blocking the renin-angiotensin system can permanently interfere with the development of radiation nephropathy even when treatment is started weeks after irradiation and/or is not continued indefinitely. These latter findings cast considerable doubt on the standard mechanistic explanations for late radiation injuries, and suggest that injuries caused by radiation therapy, radiation accidents or nuclear terrorism could be treated or prevented with post-irradiation pharmacological interventions. The specific aims of this proposal fall into four related groups: 1) Refute the hypothesis that radiation-induced activation of the renin-angiotensin system is the proximal mechanistic cause of radiation nephropathy. 2) Confirm the hypothesis that prophylaxis and treatment of radiation nephropathy with ACE inhibitors and AII blockers operate by different mechanisms. 3) Determine the mechanistic basis for the efficacy of ACE inhibitors and AII receptor blockers in the prophylaxis of radiation nephropathy. 4) Complete the randomized, prospective, trial of the use of ACE inhibitors to prevent the development of radiation nephropathy in BMT patients.