Role of Mineralocorticoid Receptor in Diabetic Cardiovascular Disease

描述（由申请人提供）：糖尿病通常与严重的心血管损伤相关。最近的数据为盐皮质激素受体（MR）激活导致糖尿病血管损伤的假设提供了支持，尽管其机制尚不确定。与这一假设一致，我们在糖尿病db/db小鼠中的临床前研究表明，阻断MR可减少白蛋白尿，并减少肾小球和肾小管间质损伤。我们在高血压、血管紧张素II（ANGII）输注动物中的研究表明，MR拮抗剂可减少血管炎症以及心脏和肾脏损伤。此外，我们的临床研究表明，在接受血管紧张素转换酶（ACE）抑制治疗的糖尿病受试者中，与氢氯噻嗪（HCTZ）治疗相比，MR拮抗剂依普利酮短期治疗可改善心肌灌注储备。这一观察结果很重要，因为它表明MR拮抗剂不是通过经典的肾脏效应发挥作用，而是通过一种额外的非容量控制依赖性机制发挥作用。本提案将检验MR激活有助于接受ACE抑制剂治疗的2型糖尿病受试者血管疾病进展的假设，因此，MR拮抗剂通过减少血管功能障碍和损伤、抑制ANGII血管效应以及改善冠状动脉循环和心脏功能发挥有益作用。为了解决这一假设，我们将在接受长期ACE抑制剂治疗的2型糖尿病和高血压受试者中进行一项前瞻性、随机、双盲研究。受试者将随机接受三种治疗之一：1）MR拮抗剂螺内酯; 2）HCTZ+钾; 3）安慰剂。我们将在两个特定目标中确定MR阻断的效果。目标1将通过测量心肌灌注储备和舒张功能评估心脏功能，目标2将评估肾血管功能。这些研究将提供有关MR拮抗剂减少糖尿病心血管损伤机制的新信息，目的是通过在ACE抑制剂治疗中加入MR阻滞剂，为糖尿病患者的心血管损伤引入新的有效治疗方法。公共卫生相关性：糖尿病是血管损伤的重要原因。血管损伤会导致许多健康问题，包括心脏损伤、肾衰竭、中风、失明和腿部血液循环不良。目前尚不完全清楚糖尿病如何导致这种损害或如何预防这种损害。最近对动物和人类的研究表明，一种称为醛固酮的血液激素（化学物质）会对血管造成损伤。这项研究的目的是确定阻断醛固酮的作用是否能改善2型糖尿病患者心脏和肾脏的血管功能，以及这是否能改善心脏功能。如果成功，这项研究将为医生提供一种新的方法来治疗血管、心脏和肾脏受损的糖尿病患者。

DESCRIPTION (provided by applicant): Diabetes mellitus is often associated with significant cardiovascular injury. Recent data provide support for the hypothesis that activation of mineralocorticoid receptor (MR) contributes to diabetic vascular injury, though the mechanisms are uncertain. Consistent with this hypothesis, our pre-clinical studies in diabetic db/db mice demonstrate that blockade of MR reduces albuminuria and decreases glomerular and tubulointerstitial injury. Our studies in hypertensive, angiotensin II (ANGII)-infused animals demonstrate that MR antagonists reduce vascular inflammation and cardiac and renal injury. Furthermore, our clinical studies show that short-term treatment with the MR antagonist eplerenone improves myocardial perfusion reserve as compared to treatment with hydrochlorothiazide (HCTZ) in subjects with diabetes receiving angiotensin-converting enzyme (ACE) inhibition therapy. This observation is important as it suggests that MR antagonists are not working via a classical renal effect, but via an additional, volume control-independent mechanism. This proposal will test the hypothesis that activation of the MR contributes to progression of vascular disease in subjects with type 2 diabetes mellitus receiving ACE inhibitor therapy, and consequently, MR antagonists exert beneficial effects by reducing vascular dysfunction and injury, inhibiting ANGII vascular effects, and improving coronary circulatory and cardiac function. To address this hypothesis we will perform a prospective randomized, double-blind study in subjects with type 2 diabetes mellitus and hypertension receiving chronic ACE inhibitor therapy. Subjects will be randomized to one of three treatments: 1) MR antagonist spironolactone; 2) HCTZ plus potassium; and 3) placebo. We will determine the effects of MR blockade in two specific aims. Aim 1 will assess cardiac function by measuring myocardial perfusion reserve and diastolic function and Aim 2 will assess renovascular function. These studies will provide new information about the mechanisms by which MR antagonists reduce diabetic cardiovascular injury, with the goal of introducing new, effective treatments of cardiovascular injury in individuals with diabetes through the addition of MR blockade to ACE inhibitor therapy. PUBLIC HEALTH RELEVANCE: Diabetes is an important cause of injury to blood vessels. Vascular injury leads to many health problems including heart damage, kidney failure, stroke, blindness and poor circulation in the legs. It is not completely known how diabetes causes this damage or how to prevent the damage. Recent studies in animals and humans suggest that a blood hormone (chemical) known as aldosterone causes damage to blood vessels. The goal of this research is to determine whether blocking the actions of aldosterone improves the function of vessels in the hearts and kidneys of patients with type 2 diabetes and whether this leads to improvements in heart function. If successful, this research will provide doctors with information about a new way to treat individuals with diabetes who have injuries to their blood vessels, heart and kidneys.