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.
The overall goal of this project is to test the hypothesis that in renal insufficiency reduction of Na/K-ATPase and sustained increase of cardiotonic steroids may cause cardiac cell death and heart chamber dilation. It will also test the role of signaling Na/K-ATPase complex in this process. The validation of these hypotheses will establish a mechanistic link between renal disease and poor cardiovascular outcomes and creates a new therapeutic target for renal insufficiency-related cardiac dysfunction.
|Drummond, Christopher A; Hill, Michael C; Shi, Huilin et al. (2016) Na/K-ATPase signaling regulates collagen synthesis through microRNA-29b-3p in cardiac fibroblasts. Physiol Genomics 48:220-9|
|Yan, Yanling; Shapiro, Joseph I (2016) The physiological and clinical importance of sodium potassium ATPase in cardiovascular diseases. Curr Opin Pharmacol 27:43-9|
|Haller, Steven T; Kumarasamy, Sivarajan; Folt, David A et al. (2016) Targeted disruption of Cd40 in a genetically hypertensive rat model attenuates renal fibrosis and proteinuria, independent of blood pressure. Kidney Int :|
|Ren, Kaili; Drummond, Christopher A; Brewster, Pamela S et al. (2016) An alternative empirical likelihood method in missing response problems and causal inference. Stat Med 35:5009-5028|
|Liu, Jiang; Tian, Jiang; Chaudhry, Muhammad et al. (2016) Attenuation of Na/K-ATPase Mediated Oxidant Amplification with pNaKtide Ameliorates Experimental Uremic Cardiomyopathy. Sci Rep 6:34592|
|Shi, Huilin; Drummond, Christopher A; Fan, Xiaoming et al. (2016) Hiding inside? Intracellular expression of non-glycosylated c-kit protein in cardiac progenitor cells. Stem Cell Res 16:795-806|
|Shah, Preeya T; Martin, Rebecca; Yan, Yanling et al. (2016) Carbonylation Modification Regulates Na/K-ATPase Signaling and Salt Sensitivity: A Review and a Hypothesis. Front Physiol 7:256|
|Feyh, Andrew; Bracero, Lucas; Lakhani, Hari Vishal et al. (2016) Role of Dietary Components in Modulating Hypertension. J Clin Exp Cardiolog 7:|
|Yan, Yanling; Shapiro, Anna P; Mopidevi, Brahma R et al. (2016) Protein Carbonylation of an Amino Acid Residue of the Na/K-ATPase Î±1 Subunit Determines Na/K-ATPase Signaling and Sodium Transport in Renal Proximal Tubular Cells. J Am Heart Assoc 5:|
|Tuttle, Katherine R; Dworkin, Lance D; Henrich, William et al. (2016) Effects of Stenting for Atherosclerotic Renal Artery Stenosis on eGFR and Predictors of Clinical Events in the CORAL Trial. Clin J Am Soc Nephrol 11:1180-8|
Showing the most recent 10 out of 44 publications