Mineralocorticoid Antagonism and Endothelial Dysfunction

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DESCRIPTION (provided by applicant): Cardiovascular complications are currently the major causes of mortality among patients with autosomal dominant polycystic kidney disease (ADPKD). Therefore, testing valid interventions to reduce morbidity and mortality within this population is of high priority. It is well documented that endothelial dysfunction coupled with abnormalities in markers of oxidative stress and inflammation develops early in ADPKD even before there is a significant decline in kidney function. Aldosterone levels are increased in patients with ADPKD and may contribute to cardiovascular disease by impairing endothelial function, and reducing vascular compliance. Of note, aldosterone antagonists have been shown to improve endothelial dysfunction in a number of studies in other patient populations. However, there has been no clinical interventional studies specifically targeting endothelial dysfunction in ADPKD. Our main goal is to establish the efficacy of an aldosterone antagonist (spironolactone) for treating vascular endothelial dysfunction and large elastic artery stiffness in ADPKD patients with preserve kidney function. A key secondary goal is to determine the integrative physiological (i.e., whole limb/artery to molecular) mechanisms underlying the beneficial effects of spironolactone. Working Hypotheses: 1. Six months of an aldosterone antagonist will increase endothelium-dependent dilation (EDD) and reduce large elastic artery stiffness in ADPKD patients with preserve kidney function. 2. The improvements in EDD after aldosterone antagonist will be associated with reduced circulating and endothelial cell markers of oxidative stress and inflammation. 3. The improvements in large elastic artery stiffness after aldosterone antagonist will be associated with reduced circulating and endothelial cell markers of oxidative stress and inflammation, and changes in markers of structural protein turnover. Impact on the Field: The expected results will provide the first insight into the: * Efficacy of an aldosterone antagonist for the primary treatment of vascular dysfunction in ADPKD patients with preserve kidney function. * Cellular and molecular physiological mechanisms by which these treatment benefits are conferred. !!