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Receptor Na/K-ATPase Antagonists As Novel Therapeutics For Renal/Cardiac Diseases

受体 Na/K-ATP 酶拮抗剂作为肾病/心脏病的新型疗法

基本信息

批准号：
8811269
负责人：
JOSEPH Isaac SHAPIRO
金额：
$ 53.57万
依托单位：
MARSHALL UNIVERSITY
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：
2011-08-18 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8811269
关键词：
1-Phosphatidylinositol 3-Kinase Abbreviations Address Affinity Agonist Angiotensin II Animals Antibodies Attenuated Binding Biology Blood Pressure Cardiac Cardiac Glycosides Cardiomyopathies Cell Culture Techniques Cells Chronic Chronic Kidney Failure Clinical Complex Congestive Heart Failure Cultured Cells Diet Dominant-Negative Mutation Effectiveness Endocytosis Fibrosis Fluorescence Functional disorder Generations Goals Heart Heart Diseases Heart Hypertrophy ITPR1 gene In Vitro Inositol Ion Pumps Kidney Kidney Diseases Kidney Failure Lesion Ligands Mediating Modeling Mus Muscle Cells Na(+)-K(+)-Exchanging ATPase Nephrectomy Organ Ouabain Pathogenesis Pathway interactions Peptides Play Protein Kinase Protein Kinase C Proteins Rattus Reactive Oxygen Species Receptor Activation Regulation Research Resistance Risk Factors Role Series Signal Transduction Sodium Chloride Solid Steroid Receptors Stimulus Stress Testing Therapeutic Transgenic Mice Transgenic Organisms base in vitro activity in vivo marinobufagenin novel novel therapeutics prevent receptor receptor function small molecule tool tripolyphosphate

项目摘要

DESCRIPTION (provided by applicant): We find that the Na/K-ATPase has an ion pumping-independent receptor function. Specifically, it associates with Src to form a receptor complex. Binding of cardiotonic steroids to this receptor complex activates Src, which, in turn, initiates a series of signaling cascades including the generation of reactive oxygen species (ROS) and the activation of PI3K/Akt pathways in renal and cardiac cells. Moreover, we demonstrate a significant increase in circulating CTS in rat model of uremic cardiomyopathy induced by 5/6 nephrectomy (PNx). Neutralization of this increase in CTS reduced ROS stress and diminished cardiomyopathy characterized by myocyte hypertrophy and cardiac fibrosis. Thus, we hypothesize that chronic stimulation of this newly appreciated receptor mechanism by elevated CTS may be the cause of the cardiac remodeling observed in uremic rats. Conversely, inhibition of the receptor function could attenuate the pathological changes in the target organs under this and other clinical conditions where CTS are elevated. Recently, we have developed several new tools that allow us to further test these hypotheses in vivo. First, we find that the N-terminus (NT) of a1 subunit acts as a dominant negative mutant capable of inhibiting CTS-induced signal transduction. Second, NT transgenic mice, in contrast to their wild-type littermates, are resistant to high salt diet-induced structural damages in the heart and in the kidney. Third, we have developed a peptide antagonist of receptor Na/K-ATPase/Src complex and demonstrated its effectiveness in vitro and in vivo. Finally, we have identified a novel class of small molecule antagonists that prevent ouabain from activating protein kinases in cell cultures. Therefore, we propose the following three specific aims. Aim 1 will test whether that chronic stimulation of the ion pumping-independent receptor function of Na/K-ATPase by CTS could result in pathological changes in the heart and the kidney. Aim 2 will address whether inhibition of Na/K-ATPase- mediated signal transduction by NT or pNaKtide attenuates high salt- and PNx-induced remodeling. In aim 3 we will further characterize the in vitro and in vivo activity of MB5 as a new class of CTS antagonists and test the in vivo effectiveness of MB5 in conferring resistance to CTS-induced organ damage. The completion of these three specific aims would significantly advance our understanding of endogenous CTS and Na/K- ATPase-mediated signal transduction in animal pathophysiology. Moreover, it would provide proof of the concept that antagonists of the receptor Na/K-ATPase can actually reduce renal and cardiac damages.

描述(申请人提供)：我们发现Na/K-ATPase具有离子泵不依赖的受体功能。具体地说，它与Src结合形成受体复合体。强心激素与这个受体复合体的结合激活了Src，进而启动了一系列的信号级联反应，包括在肾细胞和心肌细胞中产生活性氧(ROS)和激活PI3K/Akt通路。此外，在5/6肾切除(PNX)诱导的尿毒症心肌病大鼠模型中，循环CTS显著增加。CTS的这种增加的中和减少了ROS应激，并减轻了以心肌细胞肥大和心肌纤维化为特征的心肌病。因此，我们推测，CTS升高对这种新认识的受体机制的慢性刺激可能是尿毒症大鼠心脏重构的原因。相反，在CTS升高的这种和其他临床条件下，抑制受体功能可以减轻靶器官的病理变化。最近，我们开发了几种新的工具，使我们能够在体内进一步测试这些假说。首先，我们发现A1亚基的N末端(NT)是一个显性负性突变体，能够抑制CTS诱导的信号转导。其次，与野生型小鼠相比，NT转基因小鼠对高盐饮食导致的心脏和肾脏结构损伤具有抵抗力。第三，我们开发了受体Na/K-ATPase/Src复合体的多肽拮抗剂，并在体内外验证了其有效性。最后，我们确定了一类新的小分子拮抗剂，可以阻止哇巴因激活细胞培养中的蛋白激酶。因此，我们提出以下三个具体目标。目的1检测CTS对Na/K-ATPase离子泵非依赖性受体功能的慢性刺激是否会导致心脏和肾脏的病理改变。目的2探讨NT或pNaKtie抑制Na/K-ATPase介导的信号转导是否减弱高盐和PNX诱导的重塑。在目标3中，我们将进一步研究MB5作为一类新的CTS拮抗剂的体外和体内活性，并测试MB5在抵抗CTS诱导的器官损伤方面的体内有效性。这三个目标的完成将极大地促进我们对内源性CTS和Na/K-ATPase介导的信号转导在动物病理生理中的理解。此外，它将为受体Na/K-ATPase拮抗剂实际上可以减少肾脏和心脏损害的概念提供证据。

项目成果

期刊论文数量（49）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Rapamycin Attenuates Cardiac Fibrosis in Experimental Uremic Cardiomyopathy by Reducing Marinobufagenin Levels and Inhibiting Downstream Pro-Fibrotic Signaling.

DOI：
10.1161/jaha.116.004106
发表时间：
2016-09-30
期刊：
Journal of the American Heart Association
影响因子：
5.4
作者：
Haller ST;Yan Y;Drummond CA;Xie J;Tian J;Kennedy DJ;Shilova VY;Xie Z;Liu J;Cooper CJ;Malhotra D;Shapiro JI;Fedorova OV;Bagrov AY
通讯作者：
Bagrov AY

Body sodium, potassium and water in peritoneal dialysis-associated hyponatremia.

腹膜透析相关低钠血症中体内的钠、钾和水。

DOI：
10.3747/pdi.2012.00201
发表时间：
2014
期刊：
Peritoneal dialysis international : journal of the International Society for Peritoneal Dialysis
影响因子：
0
作者：
Sun,Yijuan;Mills,David;Ing,ToddS;Shapiro,JosephI;Tzamaloukas,AntoniosH
通讯作者：
Tzamaloukas,AntoniosH

Spin Trapping: A Review for the Study of Obesity Related Oxidative Stress and Na+/K+-ATPase.

自旋捕获：肥胖相关氧化应激和 Na /K -ATP 酶研究综述。

DOI：
10.4172/2155-9899.1000505
发表时间：
2017
期刊：
Journal of clinical & cellular immunology
影响因子：
0
作者：
Nawab,Athar;Nichols,Alexandra;Klug,Rebecca;Shapiro,JosephI;Sodhi,Komal
通讯作者：
Sodhi,Komal

Effect of CD40 and sCD40L on renal function and survival in patients with renal artery stenosis.

DOI：
10.1161/hypertensionaha.111.00685
发表时间：
2013-04
期刊：
Hypertension (Dallas, Tex. : 1979)
影响因子：
0
作者：
Haller ST;Kalra PA;Ritchie JP;Chrysochou T;Brewster P;He W;Yu H;Shapiro JI;Cooper CJ
通讯作者：
Cooper CJ

Na/K-ATPase Signaling and Salt Sensitivity: The Role of Oxidative Stress.