Mineralocorticoid Antagonism and Endothelial Dysfunction

描述（由申请人提供）：心血管并发症是目前常染色体显性多囊肾病（ADPKD）患者死亡的主要原因。因此，在这一人群中测试有效的干预措施以降低发病率和死亡率是当务之急。有充分的证据表明，内皮功能障碍与氧化应激和炎症标志物的异常在ADPKD早期甚至在肾功能显著下降之前就出现了。醛固酮水平在ADPKD患者中升高，可能通过损害内皮功能和降低血管顺应性而导致心血管疾病。值得注意的是，醛固酮拮抗剂在其他患者群体的许多研究中已被证明可以改善内皮功能障碍。然而，目前还没有专门针对血管内皮功能障碍的临床介入研究

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. !!