Mineralocorticoid Antagonism and Endothelial Dysfunction

描述（由申请方提供）：心血管并发症目前是常染色体显性多囊肾病（ADPKD）患者死亡的主要原因。因此，测试有效的干预措施，以减少发病率和死亡率在这一人群中是高度优先事项。有充分证据表明，内皮功能障碍伴氧化应激和炎症标志物异常在ADPKD早期甚至在肾功能显著下降之前就已出现。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，在其他患者人群的许多研究中，醛固酮拮抗剂已显示出改善内皮功能障碍。然而，还没有专门针对血管内皮功能障碍的临床干预研究。 ADPKD。我们的主要目的是确定醛固酮拮抗剂（螺内酯）治疗保留肾功能的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综合生理（即，整个肢体/动脉到分子）的机制。 工作假设： 1.在保留肾功能的ADPKD患者中，6个月的醛固酮拮抗剂将增加内皮依赖性舒张（EDD）并降低大动脉弹性硬度。 2.醛固酮拮抗剂治疗后EDD的改善与氧化应激和炎症的循环和内皮细胞标志物的减少有关。 3.醛固酮拮抗剂治疗后大弹性动脉僵硬度的改善与氧化应激和炎症的循环和内皮细胞标志物减少以及结构蛋白转换标志物的变化有关。 对实地的影响：预期结果将提供对以下方面的初步了解： * 醛固酮拮抗剂对保留肾功能的ADPKD患者血管功能障碍的初步治疗效果 * 细胞和分子生理学机制，这些治疗的好处是赋予。!!

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. !!