Targeting Sympathetic Overactivity in CKD patients: Mechanisms & Novel Therapies

 描述(申请人提供)：慢性肾脏病(CKD)患者死于心血管并发症的人数多于进展为终末期肾脏疾病的患者。交感神经系统过度活跃和高血压是慢性肾脏病的心血管危险因素。交感神经活动(SNA)的增加不仅可能导致高血压，而且还会加速终末器官损伤(肾脏、心脏和血管系统)的进展，这种损害不依赖于血压(BP)的任何升高。因此，交感神经系统构成了改善CKD患者心血管结局的主要药物靶点。然而，在确定CKD患者SNA升高的机制方面所做的工作有限。我们提出了一个全面的计划来检验这一新的假设，即内源性一氧化氮合酶抑制剂不对称二甲基精氨酸(ADMA)的积累构成了CKD交感神经过度活动的主要机制。我们的重点是透析前CKD患者(高血压CKD 3期和4期)，以干预和抵消这一群体中存在的实质性心血管风险。我们还考虑了氧化应激增加ADMA并导致CKD患者高SNA的潜在作用，因为氧化应激在这些患者中升高，这可能通过抑制ADMA的分解而增加ADMA，并具有直接的交感兴奋效应。鉴于2型糖尿病(T2D)在CKD人群中的患病率增加，以及T2D增加ADMA和氧化应激的能力，我们将研究有T2D和没有T2D的CKD患者，以更好地了解这些途径及其在CKD人群中增加ADMA和SNA的潜力(目标1)。目的1确定急性应用L精氨酸克服内源性肾上腺髓质素蓄积是否降低慢性肾功能不全患者的SNA。接下来，为了提供直接的临床应用并进一步检验ADMA在提升SNA中的作用，我们将进行一项双盲、随机、安慰剂对照的交叉设计研究，包括在T2D CKD患者中使用4周的安慰剂和吡格列酮(目标2)。最近的研究表明，吡格列酮可以减少ADMA。我们将使用显微神经学直接测量SNA，使用血浆和细胞内ADMA测量，使用电子顺磁共振波谱测量活性氧物种，以及血压和腿部血流(双功多普勒超声)。健康的性别-年龄-体重匹配的对照组将被研究进行基线比较。总体而言，我们提出了互补策略的混合，以全面探讨ADMA在调节CKD患者交感神经过度活动中的作用。我们的方法将为CKD中驱动SNA的潜在主要机制提供明确的作用，以前的研究曾建议SNA是一个强有力的候选，但尚未经过严格的测试。同时，我们将提供直接的治疗信息，通过确定现成的药物吡格列酮是否可以提供一种新的治疗方法来减少CKD患者的ADMA和交感神经过度活动，以及这是否伴随着肾功能的改善。

 DESCRIPTION (provided by applicant): More patients with chronic kidney disease (CKD) die of cardiovascular complications than progress to end stage renal disease. An overactive sympathetic nervous system and hypertension are known cardiovascular risk factors present in CKD. The increase in sympathetic nerve activity (SNA) may not only contribute to hypertension, but also accelerate the progression of end organ damage (kidney, heart, and vasculature) that is independent of any rise in blood pressure (BP). Thus, the sympathetic nervous system constitutes a primary drug target for improving cardiovascular outcomes in CKD patients. However, limited effort has been directed at identifying the mechanisms driving elevated SNA in CKD. We propose a comprehensive plan to test the novel hypothesis that accumulation of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) constitutes a major mechanism for sympathetic overactivity in CKD. Our emphasis is on pre-dialysis CKD patients (hypertensive CKD stage 3 and 4) in order to intervene and offset the substantial cardiovascular risk present in this group. We also consider a potential role for oxidative stress i increasing ADMA and contributing to high SNA in CKD, because oxidative stress is elevated in these patients and this may increase ADMA by inhibiting its breakdown as well as having direct sympatho-excitatory effects. Given the increased prevalence of Type 2 Diabetes Mellitus (T2D) in the CKD population, and the ability of T2D to also increase ADMA as well as oxidative stress, we will study CKD patients with and without T2D to better understand these pathways and their potential to increase ADMA and SNA in the CKD population (Aim 1). Aim 1 will determine whether acute L-arginine infusion to overcome the accumulation of endogenous ADMA reduces SNA in CKD patients. Next, to provide immediate clinical application and further examine the role of ADMA in elevating SNA, we will perform a double-blinded, randomized, placebo controlled crossover design study including 4 weeks of placebo and pioglitazone in T2D CKD patients (Aim 2). Recent work indicates that pioglitazone reduces ADMA. We will use microneurography for direct measures of SNA, plasma and intracellular ADMA measures, electron paramagnetic resonance spectroscopy for measures of reactive oxygen species, along with BP and leg blood flow (duplex Doppler ultrasound). Healthy sex-age-weight matched controls will be studied for baseline comparisons. Overall, we propose a blend of complementary strategies to comprehensively probe the role of ADMA in mediating sympathetic overactivity in CKD patients. Our approach will provide a definitive role for a potential major mechanisms driving SNA in CKD, which has been suggested by previous studies as a strong candidate, but not rigorously tested. At the same time we will provide direct therapeutic information by determining whether pioglitazone, a readily available drug, may provide a novel treatment for reducing ADMA and sympathetic overactivity in CKD patients and if this is accompanied by an improvement in renal function.