Mechanisms of oxidative DNA damage by endogenous substances

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Background: Only approximately half of the cancer cases in developed countries can be explained by an assured exposition to chemicals or by a genetic predisposition. Pathological processes of the body could be involved in the initiation of the other half of the cases. In the increase of the kidney cancer incidence of hypertensive individuals, raised levels of the blood pressure-regulating hormones angiotensin II and aldosterone might play a role. Up to now we have found genotoxic effects of these two compounds in vitro as well as in vivo in the kidney. During the last project period we could definitely show that the genotoxic effects are independent from blood pressure.Project content: The enzyme responsible for the increased oxidative stress caused by angiotensin II will be identified. To achieve this, animals will be utilized which lack each another isoform of the superoxide or hydrogen peroxide producing NADPH oxidase. In the case of the isoform 4, where we obtained first results, besides the global knockout animal an inducible knockout model needs to be studied, since the global knockout already showed DNA damage and impaired kidney function without angiotensin II treatment. Additionally, the activation of the cellular antioxidative defense by angiotensin II will be thoroughly studied. This will provide an insight on the possible beneficial effects of an induction of the defense system.Goal: In the course of this last project part, the identification of the source of the oxidative stress and the analysis of the antioxidative defense are supposed to provide two possible targets for a pharmacological intervention to reduce DNA damage caused by angiotensin II. First activators of the antioxidative defense will be tested.