Mitochondrial Dysfunction in Chronic Kidney Disease

描述（由申请人提供）：慢性肾脏疾病（CKD）影响美国约2600万人。终末期肾病（ESRD）是CKD的最后阶段，需要肾脏替代治疗，如血液透析（HD）。接受HD的患者发生心血管并发症的风险增加，并且传统的心血管风险因素无法解释这种风险。其他因素，如炎症和氧化应激可能有助于与终末期肾病患者的心血管事件的病理生理。我们先前已经证明缓激肽在HD患者的炎症中起作用，并在体外增加氧化应激。线粒体是氧化应激的主要来源之一;然而，线粒体功能障碍在ESRD中的作用尚不清楚。本研究的总体目标是确定进行性CKD和血液透析期间激肽释放酶-激肽系统激活对线粒体功能障碍发展的作用;我们将使用金标准方法31 P磁共振波谱测量线粒体功能。在具体目标1中，我们将检验线粒体功能随肾脏疾病进展而恶化的假设。我们将比较接受慢性HD的患者、尚未接受HD的CKD患者和无CKD的对照受试者。参与者将根据年龄、性别、糖尿病状态和BMI进行匹配。在具体目标2中，我们将检验内源性缓激肽促进HD患者线粒体功能障碍的假设。我们将首先进行一项随机、安慰剂对照、双盲、交叉研究，测量HOE-140（Icatibant）（一种缓激肽B2受体阻滞剂）对线粒体功能的影响。我们还将评估接受HD的患者，这些患者已接受ACE抑制剂雷米普利与ARB缬沙坦或安慰剂治疗3个月，作为正在进行的NIH资助的临床试验（NCT 00878969）的一部分。我们预计HOE-140阻断缓激肽B2受体将改善HD期间的线粒体功能;而雷米普利会增加内源性缓激肽，会使线粒体功能恶化。 候选人获得了博士学位。在肯塔基州大学获得生理学博士学位，并在范德比尔特大学完成临床药理学博士后培训。候选人研究了啮齿动物的线粒体生物学和肌肉生理学，并在CKD患者中进行了临床试验。该奖项将使候选人能够加强他在研究人类线粒体功能方面的专业知识，并获得作为医生科学家独立职业所需的技能。Nancy J. Brown博士（候选人的导师）是NIH资助的研究员，在指导医生实现科学独立方面有着成功的记录。作为临床转化科学家发展副院长（2006年至2010年），布朗博士开发了基础设施和环境，以促进初级医生科学家的成功。该机构致力于候选人职业发展计划的成功和研究计划的完成。

DESCRIPTION (provided by applicant): Chronic kidney disease (CKD) affects approximately 26 million people in the United States. End stage renal disease (ESRD), the final stage of CKD, requires renal replacement therapy such as hemodialysis (HD). Patients undergoing HD are at increased risk of developing cardiovascular complications, and this risk is not explained by traditional cardiovascular risk factors. Other factors such as inflammation and oxidative stress may contribute to the pathophysiology of cardiovascular events in patients with ESRD. We have previously shown that bradykinin plays a role in inflammation in patients on HD and increases oxidative stress in vitro. Mitochondria are one of the main sources of oxidative stress; however the role of mitochondrial dysfunction in ESRD is not yet understood. The overarching goal of this study is to determine the role of progressive CKD and the activation of the kalikrein-kinin system during HD on the development of mitochondrial dysfunction; we will measure mitochondrial function using the gold standard method, 31P magnetic resonance spectroscopy. In Specific Aim 1 we will test the hypothesis that mitochondrial function worsen with the progression of kidney disease. We will compare patients undergoing chronic HD, patients with CKD not yet on HD, and control subjects without CKD. Participants will be matched by age, sex, diabetic status, and BMI. In Specific Aim 2 we will test the hypothesis that endogenous bradykinin promotes mitochondrial dysfunction in patients undergoing HD. We will first perform a randomized, placebo-controlled, double-blind, cross-over study measuring the effect of HOE-140 (Icatibant), a bradykinin B2 receptor blocker, on mitochondrial function. We will also evaluate patients undergoing HD that have been treated for 3 months with the ACE inhibitor ramipril versus the ARB valsartan or placebo, as part of an ongoing NIH funded clinical trial (NCT00878969). We anticipate that bradykinin B2 receptor blockade with HOE-140 will improve mitochondrial function during HD; whereas ramipril, which increases endogenous bradykinin, will worsen mitochondrial function. The candidate obtained his Ph.D. in Physiology in the University of Kentucky and completed postdoctoral training in Clinical Pharmacology at Vanderbilt University. The candidate has studied mitochondrial biology and muscle physiology in rodents, and has conducted a clinical trial in patients with CKD. This award will allow the candidate to strengthen his expertise in studying mitochondrial function in humans and to acquire the skills necessary for an independent career as a physician-scientist. Dr. Nancy J. Brown (candidate's mentor) is an NIH-funded investigator with a successful record of mentoring physicians to scientific independence. As Associate Dean for Clinical Translational Scientist Development (2006 to 2010), Dr. Brown developed the infrastructure and environment to promote the success of junior physician-scientists. The institution is committed to the success of the candidate's career development plan and the completion of the research plan.