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

描述(申请人提供)：慢性肾脏疾病(CKD)与不良的心血管结局密切相关。我们最近的实验数据表明，Na/K-ATPase降低可能与肾功能不全所致的心功能不全有关。首先，我们观察到5/6肾部分切除(PNX)导致小鼠心脏Na/K-ATPase的时间依赖性降低，并伴随着心脏适应性不良的重塑和心功能的恶化。左心室最初表现为肥大生长，然后扩张，这与Na/K-ATPase表达的变化有关。第二，我们有新的证据表明，Na/K-ATPase的降低在体外加强了强心性类固醇(CTS)诱导的心肌细胞死亡，并在体内增强了扩张性心肌病。在转基因小鼠中，Na/K-ATPase的遗传降低刺激了促凋亡蛋白的表达，并加强了CTS诱导的心肌细胞死亡。它还会导致这些小鼠的收缩功能下降。第三，我们的数据显示，在正常的心肌细胞中，存在着一种自我保护机制，保护膜上Na/K-ATPase的丰度，保护细胞免于死亡。Na/K-ATPase的降低减弱了与这种自我保护相关的信号功能。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。这些研究使我们假设，Na/K-ATPase的降低和CTS的持续增加一起加强了心肌细胞的凋亡，并导致了肾功能不全时的心功能不全。为了验证这一假设，我们将在建立良好的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心肌细胞死亡相关的途径。同时，我们将进行人体研究，将肾功能和CTS释放与心脏功能障碍联系起来。

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.