Mineralocorticoid Antagonism and Endothelial Dysfunction

描述(申请人提供)：心血管并发症是目前常染色体显性遗传性多囊肾病(ADPKD)患者死亡的主要原因。因此，测试有效的干预措施以减少这一人群的发病率和死亡率是高度优先的。已有文献表明，内皮功能障碍加上氧化应激和炎症标记物的异常在ADPKD早期就会发生，甚至在肾功能明显下降之前就会发生。ADPKD患者的醛固酮水平升高，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，在其他患者群体中的一些研究表明，醛固酮拮抗剂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细胞功能障碍的临床干预研究。 ADPKD.我们的主要目标是确定一种醛固酮拮抗剂(螺内酯)对保留肾功能的ADPKD患者的血管内皮功能障碍和大弹性动脉僵硬的疗效。一个关键的次要目标是确定螺内酯有益作用的综合生理机制(即，整个肢体/动脉到分子)。 工作假设： 1.在保留肾功能的ADPKD患者中，服用6个月的醛固酮拮抗剂将增加内皮依赖性扩张(EDD)，降低大的弹性动脉僵硬。 2.醛固酮拮抗剂治疗后EDD的改善与循环和内皮细胞氧化应激和炎症标志物的减少有关。 3.应用醛固酮拮抗剂后，大弹性动脉僵硬程度的改善可能与氧化应激和炎症的循环和内皮细胞标志物的减少以及结构蛋白周转标志物的改变有关。 对实地的影响：预期结果将提供对以下方面的第一次洞察： *一种醛固酮拮抗剂对保留肾功能的ADPKD患者血管功能障碍的主要治疗效果。 *赋予这些治疗益处的细胞和分子生理机制。！！

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. !!