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Na/K-ATPase Reduction in Renal Disease-Related Cardiac Dysfunction

肾病相关心脏功能障碍中 Na/K-ATP 酶的减少

基本信息

批准号：
8966030
负责人：
Jiang Tian
金额：
$ 37.45万
依托单位：
UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-12-15 至 2018-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8966030
关键词：
Age Alleles Angiotensin II Receptor Angiotensin-Converting Enzyme Inhibitors Animal Model Animals Antibodies Apoptosis Attenuated Blood Pressure Blood specimen Cardiac Cardiac Glycosides Cardiovascular system Cell Death Cell Survival Cells Cessation of life Chronic Kidney Failure Complex Couples Data Deterioration Digibind Dilated Cardiomyopathy Functional disorder Gender Genes Genetic Goals Growth Heart Human In Vitro Kidney Kidney Diseases Kidney Failure Lead Left ventricular structure Link Measures Membrane Methods Mus Muscle Cells Myocardial dysfunction Na(+)-K(+)-Exchanging ATPase Nephrectomy Neutralization Tests Operative Surgical Procedures Outcome Pathway interactions Patients Peptides Pharmaceutical Preparations Process Randomized Controlled Clinical Trials Receptor Protein-Tyrosine Kinases Renal function Renin-Angiotensin System Role Signal Pathway Signal Transduction Testing Time Tissues Transgenic Mice United States National Institutes of Health Validation Work adjudicate attenuation heart function human study in vivo knock-down marinobufagenin mouse model new therapeutic target pro-apoptotic protein protein expression renal ischemia research study response tool uremic cardiomyopathy

项目摘要

DESCRIPTION (provided by applicant): Chronic renal disease (CKD) is closely related with poor cardiovascular outcomes. Our recent experimental data indicate that Na/K-ATPase reduction may be related with renal insufficiency-induced cardiac dysfunction. First, we have observed that 5/6th partial nephrectomy (PNx) induces a time-dependent decrease of Na/K-ATPase in the mouse heart along with maladaptive cardiac remodeling and deterioration in heart function. The left ventricle initially shows hypertrophic growth and then dilation, which correlates with changes in Na/K-ATPase expression. Second, we have new evidence demonstrating that reduction in Na/K-ATPase potentiates cardiotonic steroid (CTS)-induced cardiac cell death in vitro, and dilated cardiomyopathy in vivo. In transgenic mice, genetic reduction of Na/K-ATPase stimulates the expression of pro-apoptotic proteins and potentiates CTS-induced cardiac cell death. It also causes decreased contractile function in these mice. Third, our data have revealed that in normal cardiac cells there exists a self-protection mechanism preserving the membrane abundance of Na/K-ATPase and protecting cells from death. Reduction of Na/K-ATPase attenuates the signaling function that is related with this self-protection. Furthermore, our work demonstrates that endogenous CTS are elevated in animals and humans with renal diseases. These studies lead us to hypothesize that reduction of Na/K-ATPase together with a sustained increase in CTS potentiates myocyte apoptosis and results in cardiac dysfunctions in renal insufficiency. To test this hypothesis we will conduct experiments in a well established PNx animal model, and use transgenic mice and newly developed tools to assess the pathways that are related with myocyte death. In parallel, we will perform the human study to link renal function and CTS release to cardiac dysfunction.

描述（由申请人提供）：慢性肾脏疾病（CKD）与不良心血管结局密切相关。我们最近的实验数据表明，Na/K-ATP酶减少可能与肾功能不全引起的心功能不全有关。首先，我们已经观察到，5/6肾部分切除术（PNx）诱导小鼠心脏Na/K-ATP酶的时间依赖性降低沿着适应不良的心脏重塑和心功能恶化。左心室最初显示肥厚性生长，然后扩张，这与Na/K-ATP酶表达的变化相关。其次，我们有新的证据表明，Na/K-ATP酶的减少增强了强心类固醇（CTS）诱导的体外心脏细胞死亡和体内扩张型心肌病。在转基因小鼠中，Na/K-ATP酶的遗传减少刺激促凋亡蛋白的表达并增强CTS诱导的心脏细胞死亡。它还导致这些小鼠的收缩功能下降。第三，我们的数据表明，在正常的心肌细胞中，存在着一种自我保护机制，保护膜Na/K-ATP酶的丰度，保护细胞免于死亡。Na/K-ATP酶的减少减弱了与这种自我保护相关的信号传导功能。此外，我们的工作表明，内源性CTS在患有肾脏疾病的动物和人类中升高。这些研究使我们推测Na/K-ATP酶的减少与CTS的持续增加一起增强心肌细胞凋亡并导致肾功能不全时的心脏功能障碍。为了验证这一假设，我们将在一个完善的PNx动物模型中进行实验，并使用转基因小鼠和新开发的工具来评估与肌细胞死亡相关的途径。同时，我们将进行人体研究，以将肾功能和CTS释放与心功能不全联系起来。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Circulating CD40 and sCD40L Predict Changes in Renal Function in Subjects with Chronic Kidney Disease.

循环 CD40 和 sCD40L 可预测慢性肾病患者肾功能的变化。

DOI：
10.1038/s41598-017-08426-8
发表时间：
2017
期刊：
Scientific reports
影响因子：
4.6
作者：
Xie,JeffreyX;Alderson,Helen;Ritchie,James;Kalra,PhilipA;Xie,Yanmei;Ren,Kaili;Nguyen,Hanh;Chen,Tian;Brewster,Pamela;Gupta,Rajesh;Dworkin,LanceD;Malhotra,Deepak;Cooper,ChristopherJ;Tian,Jiang;Haller,StevenT
通讯作者：
Haller,StevenT

Reducing Cardiac Fibrosis: Na/K-ATPase Signaling Complex as a Novel Target.