The use of androgen supplements is becoming increasingly prevalent in the United States mainly in the general population of middle-aged and elderly men with chronic cardiovascular diseases, such as hypertension and type II diabetes, who receive testosterone supplements to treat osteoporosis, improve libido and feelings of well-being, and to improve sexual performance. Despite the common use of androgens, the long term impact of androgen supplements in healthy individuals, much less in individuals who suffer from chronic cardiovascular-renal diseases (CV-RD), is unknown. Recent studies from our laboratory and others indicate that endogenous androgens contribute to greater renal injury in normotensive and hypertensive male rats. However, there is little information regarding whether androgen supplements exacerbate renal injury and by what mechanisms. The overall hypothesis to be tested in this proposal is that androgen supplements exacerbate renal injury by directly increasing oxidative stress via NADPH oxidase, and hemodynamically by increasing transmission of pressure to the glomerulus. We further hypothesize that androgen supplements indirectly increase ROS by stimulating the RAS. Finally, the hypothesis will be tested that androgen supplements could activate NF-DB in the kidney promoting inflammation. In humans the two leading causes for renal injury are hypertension and type II diabetes. Therefore, studies will be performed in male rat models that mimic men who suffer from CV-RD and are prescribed androgen supplements: men with hypertensive renal injury (rats with reduced renal mass on high salt diet), and men with type II diabetes (Zucker rats), using testosterone, the most commonly prescribed androgen for men. Studies will also be performed in human male mesangial cells. The specific aims of the proposal are to test the hypotheses that: 1) androgen supplements will exacerbate renal injury in rats with hypertension or type II diabetes; 2) androgen supplements will exacerbate renal injury by increasing oxidative stress mediated by NADPH oxidase and that the intrarenal RAS plays a role in mediating androgen supplement-induced oxidative stress; 3) androgen supplements will exacerbate renal injury by activating NF-DB leading to increased inflammatory cytokines; 4) androgen supplements will exacerbate renal injury by increasing transmission of pressure to the glomerulus. [unreadable] [unreadable] [unreadable]