RENALASE DEFICIENCY AND CARDIOVASCULAR COMPLICATIONS OF CHRONIC KIDNEY DISEASE

慢性肾病的肾酶缺乏和心血管并发症

• 批准号: 7820757
• 负责人: Gary V. Desir
• 金额: $ 50万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7820757
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; American; Animal Model; Animals; Anterior; Area; Binding; Biological Markers; Blood; Blood Pressure; Cardiac; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Catecholamines; Cell Survival; Chronic Kidney Failure; Code; Development; Diagnostic; Disease; Dopamine; End stage renal failure; Enzymes; Epinephrine; Essential Hypertension; Excretory function; Flavin-Adenine Dinucleotide; Genes; Glomerular Filtration Rate; Heart; Heart Diseases; Hormones; Hour; Human; Hypertension; Injury; Kidney; Kidney Diseases; Knockout Mice; Knowledge; Laboratories; Left; Ligation; Modeling; Molecular; Mus; Myocardial; Myocardial Ischemia; National Institute of Diabetes and Digestive and Kidney Diseases; Necrosis; Norepinephrine; Pathogenesis; Pathway interactions; Patients; Plasma; Play; Prevention; Promoter Regions; Proximal Kidney Tubules; Rattus; Recombinants; Reperfusion Therapy; Research; Risk; Role; Severities; Single Nucleotide Polymorphism; Skeletal Muscle; Small Intestines; Sympathetic Nervous System; Testing; Therapeutic; Translations; Urine; amine oxidase; base; cardiovascular risk factor; falls; improved; in vivo; inhibitor/antagonist; interest; man; mouse model; new therapeutic target; normotensive; novel; patient population; public health relevance; renal ischemia; research study; tool; urinary

DESCRIPTION (provided by applicant): The challenge area (15-DK-103) is the translation of new molecules and pathways involved in pathogenesis of diseases of interest to NIDDK into potential therapies, diagnostics, or research tools. The specific challenge topic is the examination of the therapeutic utility of renalase, a novel molecule discovered in our laboratory, for the treatment of cardiovascular complications associated with chronic kidney disease. Twenty million Americans suffer from chronic kidney disease, and are at significantly greater risk for having both fatal and non-fatal cardiovascular complications. The pathogenesis of cardiac disease in this patient population is not well understood. Patients with kidney disease have a deficiency in renalase, a newly discovered enzyme that is made in the kidney, is secreted in blood, and regulates blood pressure and cardiac function. The renalase pathway is a previously unrecognized mechanism for regulating circulating catecholamines, and, therefore, cardiac function, and blood pressure. In this pathway, renalase, a novel secreted amine oxidase that is inactive at baseline, is rapidly turned on (25 fold increase) by either modest increases in blood pressure and/or brief surges in either plasma dopamine, epinephrine or norepinephrine. The active enzyme specifically degrades circulating catecholamines in vivo, causing a significant fall in blood pressure even in normotensive animals. An increase in plasma catecholamines, not only activates renalase enzymatic activity, but also leads to a 3-4 stimulation of renalase secretion. We have preliminary evidence suggesting the presence of a renalase inhibitor in plasma. The renalase knockout mouse (renalase KO) is hypertensive. Abnormalities in the renalase pathway are evident in animal models of chronic kidney disease (CKD) and hypertension. Two single nucleotide polymorphisms (SNP) in the renalase gene were found to be associated with essential hypertension in man. Blood renalase levels are inversely correlated with glomerular filtration rate (GFR) and markedly reduced in patients with advanced CKD, and end stage kidney disease (ESRD). The sympathetic nervous system is activated in CKD and ESRD, and patients have a significant increase in cardiovascular disease. We hypothesize that intracellular renalase along with that secreted into blood by the kidney (although also expressed in heart, skeletal muscle and small intestine), play a key role in regulating blood pressure and cardiovascular function, and that abnormalities in the renalase pathway contribute to the heightened cardiovascular risks observed in patients with chronic kidney disease (CKD). Based on the foregoing, we hypothesize that both intracellular and secreted renalase play a key role in regulating blood pressure and cardiovascular function, and that abnormalities in the renalase pathway contribute to the heightened cardiovascular risks observed in patients with chronic kidney disease (CKD). In the context of the overall hypothesis, we propose to examine the molecular mechanisms by which renalase deficiency predisposes to more severe ischemic renal and cardiac injury, and to explore the therapeutic utility of recombinant renalase These studies will expand our knowledge of the renalase pathway, and may identify novel therapeutic targets for the prevention and treatment of cardiovascular complications in patients with kidney disease. PUBLIC HEALTH RELEVANCE: Twenty million Americans suffer from chronic kidney disease, and are at significantly greater risk for having both fatal and non-fatal cardiovascular complications. The pathogenesis of cardiac disease in this patient population is not well understood. Patients with kidney disease have a deficiency in renalase, a newly discovered hormone that is made in the kidney, is secreted in blood, and regulates blood pressure and cardiac function. Renalase itself or components of the renalase pathway may offer valuable therapeutic options for patients with kidney disease.

描述（由申请人提供）：挑战领域（15-DK-103）是对NIDDK感兴趣疾病发病机理的新分子和途径的翻译，为潜在的疗法，诊断或研究工具。具体的挑战主题是检查肾酶的治疗效用，肾酶是我们实验室中发现的一种新型分子，用于治疗与慢性肾脏疾病有关的心血管并发症。两千万美国人患有慢性肾脏疾病，并且患有致命和非致命性心血管并发症的风险明显更大。该患者人群中心脏病的发病机理尚不清楚。肾脏疾病患者的肾酶缺乏，是一种新发现的肾脏酶，是血液分泌的，并调节血压和心脏功能。肾酶途径是调节循环儿茶酚胺的先前未认识的机制，因此是心脏功能和血压。在这一途径中，肾酶是一种新型分泌的胺氧化酶，在基线时不活跃，在血压多巴胺，肾上腺素或去甲肾上腺素中的血压和/或短暂涌现中，通过适度的血压增加和/或短暂涌现，迅速打开（25倍）。活性酶在体内特异性降解了循环的儿茶酚胺，即使在正常的动物中，血压也会显着下降。血浆儿茶酚胺的增加，不仅激活肾小球酶活性，而且还导致3-4刺激肾酶分泌。我们有初步证据表明在血浆中存在肾小球酶抑制剂。肾酶基因敲除小鼠（肾酶KO）是高血压的。肾酶途径的异常在慢性肾脏疾病（CKD）和高血压的动物模型中显而易见。发现肾小球酶基因中的两个单核苷酸多态性（SNP）与人体中的基本高血压有关。血肾酶水平与肾小球滤过率（GFR）成反比，并在晚期CKD和终阶段肾脏疾病（ESRD）的患者中显着降低。交感神经系统在CKD和ESRD中被激活，患者的心血管疾病显着增加。我们假设细胞内肾小球酶以及肾脏分泌成血液（尽管在心脏，骨骼肌肉和小肠中也表达），在调节血压和心血管功能方面起着关键作用，以及肾酶途径中的异常，导致心血管风险的较高的患者在患者中患有炎症性肾脏病患者（Ckney Seendey Seidney（Ck））。基于上述情况，我们假设细胞内和分泌的肾小球酶在调节血压和心血管功能方面都起着关键作用，并且肾酶途径的异常有助于在慢性肾脏病（CKD）患者中观察到的心血管危险升高。在总体假设的背景下，我们建议检查肾小球酶缺乏症易于更严重的缺血性肾脏和心脏损伤的分子机制，并探索重组肾酶的治疗性这些研究将扩大我们对肾小球酶途径的了解，并可能识别出针对培训的新型治疗方法，以培养核心疾病，以培养核心疾病。 公共卫生相关性：两千万美国人患有慢性肾脏疾病，并且患有致命和非致命性心血管并发症的风险明显更大。该患者人群中心脏病的发病机理尚不清楚。肾脏疾病患者的肾酶缺乏肾酶，这是一种新发现的肾脏激素，在血液中分泌，并调节血压和心脏功能。肾酶本身或肾酶途径的成分可能为肾脏疾病患者提供有价值的治疗选择。