Chronic oxidative stress and inflammation are now known to play a fundamental role in the development and progression of renal failure, heart failure, and atherosclerosis. For example, endothelial dysfunction has been shown to result directly from excessive levels of reactive oxygen species stimulated by angiotensin II. Induction of antioxidant systems in the kidney, particularly the expression of inducible heme oxygenase (HO-1), has been repeatedly shown to be beneficial in models of hypertension, renal dysfunction, and renal failure. Oxidative stress in the endothelium is also understood to be fundamental to the formation and progression of atherosclerotic plaques, and atherosclerosis is now acknowledged to be primarily an inflammatory condition. Similarly, oxidative stress and inflammation in skeletal muscle and heart muscle are believed to play a primary role in the development of insulin resistance and heart failure.
Because of their exceptionally potent induction of Nrf2-mediated antioxidant systems, including HO-1 expression, AIMs show great promise for the treatment of these disorders. Initial preclinical studies have demonstrated that AIMs have potent protective activity in models of renal ischemia-reperfusion injury. Observations from other preclinical studies, and from clinical trials of RTA 402, also support the use of AIMs in the treatment of renal disease. Due to the very high level of unmet need in patients with renal failure, this indication has been selected for initial clinical studies.
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