Targeting Sympathetic Overactivity in CKD patients: Mechanisms & Novel Therapies

 描述（由申请方提供）：死于心血管并发症的慢性肾病（CKD）患者多于进展为终末期肾病的患者。交感神经系统过度活跃和高血压是CKD中存在的已知心血管风险因素。交感神经活动（SNA）的增加不仅可能导致高血压，还可能加速与血压（BP）升高无关的终末器官损伤（肾脏、心脏和血管系统）的进展。因此，交感神经系统是改善CKD患者心血管结局的主要药物靶点。然而，有限的努力已经针对确定机制驱动SNA升高CKD。我们提出了一个全面的计划来测试新的假设，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交感神经过度活跃的主要机制。我们的重点是透析前CKD患者（高血压CKD 3期和4期），以干预和抵消该组中存在的重大心血管风险。我们还考虑了氧化应激的潜在作用，即增加ADMA并导致CKD中的高SNA，因为这些患者的氧化应激升高，这可能通过抑制其分解以及直接的交感神经兴奋作用来增加ADMA。鉴于CKD人群中2型糖尿病（T2 D）的患病率增加，以及T2 D也增加ADMA和氧化应激的能力，我们将研究伴和不伴T2 D的CKD患者，以更好地了解这些途径及其增加CKD人群中ADMA和SNA的潜力（目的1）。目的1将确定急性L-精氨酸输注以克服内源性ADMA的积累是否会降低CKD患者的SNA。接下来，为了提供即时临床应用并进一步检查ADMA在提高SNA中的作用，我们将在T2 D CKD患者中进行一项双盲、随机化、安慰剂对照交叉设计研究，包括安慰剂和吡格列酮治疗4周（目的2）。最近的研究表明，吡格列酮减少ADMA。我们将使用显微神经造影术直接测量SNA，血浆和细胞内ADMA测量，电子顺磁共振光谱测量活性氧，沿着BP和腿部血流（多普勒超声）。将对健康的性别-年龄-体重匹配对照进行研究，以进行基线比较。总的来说，我们提出了一个互补的策略，全面探讨ADMA介导的交感神经过度活跃的CKD患者的作用。我们的方法将提供一个潜在的主要机制驱动SNA在CKD，这已被建议由以前的研究作为一个强有力的候选人，但没有严格的测试确定的作用。与此同时，我们将通过确定吡格列酮（一种易得药物）是否可提供一种降低CKD患者ADMA和交感神经过度活跃的新型治疗方法，以及是否伴有肾功能改善，提供直接的治疗信息。

 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.