RENALASE DEFICIENCY AND CARDIOVASCULAR COMPLICATIONS OF CHRONIC KIDNEY DISEASE

描述（由申请人提供）：挑战领域（15-DK-103）是将NIDDK感兴趣的疾病发病机制中涉及的新分子和途径转化为潜在的疗法、诊断或研究工具。具体的挑战主题是检查肾酶的治疗效用，肾酶是我们实验室发现的一种新分子，用于治疗与慢性肾脏疾病相关的心血管并发症。2000万美国人患有慢性肾脏疾病，并且患有致命和非致命心血管并发症的风险显著更高。该患者人群中心脏病的发病机制尚不清楚。肾脏疾病患者缺乏肾酶，肾酶是一种新发现的酶，在肾脏中产生，在血液中分泌，调节血压和心脏功能。肾酶途径是以前未认识到的调节循环儿茶酚胺的机制，因此，心脏功能和血压。在该途径中，肾酶（一种在基线时无活性的新型分泌型胺氧化酶）通过血压的适度升高和/或血浆多巴胺、肾上腺素或去甲肾上腺素的短暂激增而迅速开启（增加25倍）。这种活性酶在体内特异性降解循环中的儿茶酚胺，即使在血压正常的动物中也能引起血压的显著下降。血浆儿茶酚胺的增加不仅激活肾酶的酶活性，而且导致肾酶分泌的3-4刺激。我们有初步证据表明血浆中存在肾酶抑制剂。肾酶敲除小鼠（肾酶KO）是高血压的。肾酶途径的阻断在慢性肾病（CKD）和高血压的动物模型中是明显的。肾酶基因的两个单核苷酸多态性（single nucleotide polymorphism，SNP）与人类原发性高血压相关，肾酶水平与肾小球滤过率（glomerular filtration rate，GFR）呈负相关，在晚期CKD和终末期肾病（end stage kidney disease，ESRD）患者中显著降低。CKD和ESRD患者的交感神经系统被激活，患者的心血管疾病显著增加。我们假设，细胞内肾酶沿着肾脏分泌到血液中的肾酶（尽管也在心脏、骨骼肌和小肠中表达）在调节血压和心血管功能中起关键作用，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风险升高。基于上述，我们假设细胞内和分泌的肾酶在调节血压和心血管功能中起关键作用，肾酶途径的异常有助于在慢性肾脏疾病（CKD）患者中观察到的心血管风险增加。在总体假设的背景下，我们建议检查肾酶缺乏易患更严重的缺血性肾和心脏损伤的分子机制，并探讨重组肾酶的治疗效用。这些研究将扩大我们对肾酶途径的了解，并可能确定新的治疗靶点，用于预防和治疗肾脏疾病患者的心血管并发症。 公共卫生相关性：2000万美国人患有慢性肾脏疾病，并且患有致命和非致命心血管并发症的风险显著更高。该患者人群中心脏病的发病机制尚不清楚。肾脏疾病患者缺乏肾酶，肾酶是一种新发现的激素，在肾脏中产生，在血液中分泌，调节血压和心脏功能。肾酶本身或肾酶途径的组分可能为肾病患者提供有价值的治疗选择。

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.