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.
Bardoxolone methyl, previously known as RTA
402, has advanced to late stage clinical development for chronic
kidney disease. In the separate clinical trials, this agent has
been shown to improve patients' renal function as measured by
estimated glomerular filtration rate. Improvements were also seen
in measures of glycemic control, creatinine clearance, cystatin C,
and uric acid. Results were presented in two separate oral
presentations at the 2009 meeting of the American Diabetes
Association.
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