Regulation of Blood Pressure by Klotho

Klotho 调节血压

• 批准号: 8622211
• 负责人: Zhongjie Sun
• 金额: $ 64.04万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-15 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8622211
• 关键词: ATP phosphohydrolase; Abbreviations; Age; Age-Years; Aging; Aging-Related Process; Attenuated; Blood Pressure; Blood Pressure Monitors; Blood Vessels; Cadherins; Cardiovascular Diseases; Cardiovascular system; Cells; Cleaved cell; Data; Dependovirus; Development; Disintegrins; Distal convoluted renal tubule structure; Endothelial Cells; Environment; Epithelial Cells; Excretory function; Gene Delivery; Gene Expression; Gene Mutation; Genes; Goals; High Prevalence; Human; Hypertension; Inbred SHR Rats; Kidney; Knock-out; Longevity; Maintenance; MicroRNAs; Mus; Mutation; Myocardial Infarction; NADPH Oxidase; Na(+)-K(+)-Exchanging ATPase; Pathogenesis; Phenotype; Play; Population; Premature aging syndrome; Prevalence; Prevention strategy; Regulation; Research; Risk Factors; Role; SLC12A3 gene; Smooth Muscle Myocytes; Sodium Chloride; Stroke; Suppressor Genes; Telemetry; Testing; Therapeutic; Time; Tissues; Transgenes; Up-Regulation; Vascular Diseases; Work; aged; aging gene; anti aging; blood pressure regulation; cell type; endothelial dysfunction; hypertension control; improved; in vivo; insight; klotho protein; knockout gene; mortality; novel; novel strategies; novel therapeutic intervention; overexpression; pre-B-cell colony-enhancing factor protein; promoter; public health relevance; receptor; recombinase; vascular endothelial dysfunction

DESCRIPTION (provided by applicant): Klotho is a recently-discovered anti-aging gene. Genetic mutation of klotho results in multiple premature aging phenotypes. In contrast, mice that overexpress klotho enjoy an extended lifespan. Thus, klotho may be an aging-suppressor gene that can delay aging when over expressed and accelerate aging when disrupted. Cardiovascular disease is associated with aging. For instance, the prevalence of hypertension increases with age while the level of the circulating klotho declines with age. It is not known, however, if klotho is involved in the maintenance of blood pressure. Whether klotho gene deficiency causes hypertension has never been determined. Klotho is predominately expressed in the renal distal convoluted tubule (DCT) epithelial cells although it is also found in a few of other types of cells or tissues. Kidney-specific knockout of klotho gene (KL-KO) was achieved using a cadherin promoter-Cre recombinase transgene and the loxP-flanked klotho gene. Our new exciting preliminary data showed that kidney-specific conditional KL-KO impaired renal Na excretion and vascular endothelial function and increased blood pressure (BP) significantly in mice. The level of the circulating klotho protein was decreased in spontaneous hypertensive rats (SHR). The objective of the proposed research is to determine if klotho plays a role in the maintenance of BP and if klotho deficiency is involved in the pathogenesis of hypertension. This objective will be achieved by pursuing three interrelated specific aims using a combination of several novel approaches including kidney-specific conditional gene knockout, in vivo DCT- and endothelial cell-specific gene delivery, and real-time monitoring of blood pressure (telemetry). The specific aims are: (1) Determine if klotho plays a role in the maintenance of blood pressure by testing the effect of kidney-specific conditional KL-KO on Na excretion, endothelial function, and blood pressure. (2) Determine a novel role of klotho in the regulation of Na-Cl cotransporter (NCC) and Na, K-ATPase (ATPase) in the DCT cells in kidneys. (3) Determine the role of the circulating klotho in the development of spontaneous hypertension and vascular dysfunction by DCT-specific gene delivery of ADAM10, a disintegrin that cleaves and releases klotho from DCT cells. These studies will demonstrate, for the first time, important roles of klotho in the maintenance of blood pressure and in the pathogenesis of hypertension. The results will provide novel mechanism that klotho protects the cardiovascular system. Completion of the project may reveal new insights into therapeutic strategies for hypertension and related cardiovascular disorders. PUBLIC HEALTH RELEVANCE: Cardiovascular disease is associated with aging. For instance, the prevalence of hypertension increases with age. The purpose of the proposed research is to determine the role of klotho, a recently-discovered anti-aging gene, in the regulation of blood pressure and in the pathogenesis of spontaneous hypertension. The results will provide novel information that klotho protects the cardiovascular system. Completion of the project may offer a new therapeutic approach for hypertension and related cardiovascular disorders. The finding will benefit the US population which has a high prevalence of hypertension.

描述（申请人提供）：Klotho是一种新近发现的抗衰老基因。 klotho 基因突变导致多种早衰表型。相比之下，过度表达 klotho 的小鼠寿命更长。因此，klotho可能是一种衰老抑制基因，当过度表达时可以延缓衰老，而当被破坏时则加速衰老。心血管疾病与衰老有关。例如，高血压的患病率随着年龄的增长而增加，而循环克洛托的水平则随着年龄的增长而下降。然而，尚不清楚克洛索是否参与维持血压。 klotho基因缺陷是否会导致高血压尚未确定。 Klotho 主要在肾远曲小管 (DCT) 上皮细胞中表达，尽管它也在一些其他类型的细胞或组织中发现。使用钙粘蛋白启动子-Cre重组酶转基因和loxP侧翼的klotho基因实现了klotho基因的肾脏特异性敲除（KL-KO）。我们新的令人兴奋的初步数据表明，肾脏特异性条件性 KL-KO 会损害小鼠肾钠排泄和血管内皮功能，并显着升高血压 (BP)。自发性高血压大鼠（SHR）中循环 klotho 蛋白的水平降低。本研究的目的是确定 klotho 是否在维持血压方面发挥作用，以及 klotho 缺乏是否与高血压的发病机制有关。这一目标将通过结合多种新方法来实现三个相互关联的具体目标，包括肾脏特异性条件基因敲除、体内 DCT 和内皮细胞特异性基因传递以及血压实时监测（遥测）。具体目标是：（1）通过测试肾脏特异性条件KL-KO对Na排泄、内皮功能和血压的影响，确定klotho是否在维持血压中发挥作用。 (2) 确定 klotho 在调节肾脏 DCT 细胞中 Na-Cl 协同转运蛋白 (NCC) 和 Na,K-ATP 酶 (ATPase) 中的新作用。 (3) 通过 ADAM10（一种从 DCT 细胞裂解并释放 klotho 的解整合素）的 DCT 特异性基因传递，确定循环 klotho 在自发性高血压和血管功能障碍的发展中的作用。这些研究将首次证明 klotho 在维持血压和高血压发病机制中的重要作用。研究结果将为klotho保护心血管系统提供新的机制。该项目的完成可能会揭示高血压和相关心血管疾病治疗策略的新见解。 公共卫生相关性：心血管疾病与衰老有关。例如，高血压的患病率随着年龄的增长而增加。本研究的目的是确定 klotho（一种最近发现的抗衰老基因）在血压调节和自发性高血压发病机制中的作用。结果将提供 klotho 保护心血管系统的新信息。该项目的完成可能为高血压和相关心血管疾病提供一种新的治疗方法。这一发现将使高血压患病率较高的美国人口受益。