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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
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Lathrop, David A
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University of Toledo
Internal Medicine/Medicine
Schools of Medicine
United States
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Xie, Jeffrey X; Zhang, Shungang; Cui, Xiaoyu et al. (2018) Na/K-ATPase/src complex mediates regulation of CD40 in renal parenchyma. Nephrol Dial Transplant 33:1138-1149
Roumelioti, Maria-Eleni; Glew, Robert H; Khitan, Zeid J et al. (2018) Fluid balance concepts in medicine: Principles and practice. World J Nephrol 7:1-28
Lakhani, Hari Vishal; Khanal, Tilak; Gabi, Alaa et al. (2018) Developing a panel of biomarkers and miRNA in patients with myocardial infarction for early intervention strategies of heart failure in West Virginian population. PLoS One 13:e0205329
Crotty Alexander, Laura E; Drummond, Christopher A; Hepokoski, Mark et al. (2018) Chronic inhalation of e-cigarette vapor containing nicotine disrupts airway barrier function and induces systemic inflammation and multiorgan fibrosis in mice. Am J Physiol Regul Integr Comp Physiol 314:R834-R847
Drummond, Christopher A; Brewster, Pamela S; He, Wencan et al. (2017) Cigarette smoking and cardio-renal events in patients with atherosclerotic renal artery stenosis. PLoS One 12:e0173562
Alaini, Ahmed; Malhotra, Deepak; Rondon-Berrios, Helbert et al. (2017) Establishing the presence or absence of chronic kidney disease: Uses and limitations of formulas estimating the glomerular filtration rate. World J Methodol 7:73-92
Sodhi, Komal; Srikanthan, Krithika; Goguet-Rubio, Perrine et al. (2017) pNaKtide Attenuates Steatohepatitis and Atherosclerosis by Blocking Na/K-ATPase/ROS Amplification in C57Bl6 and ApoE Knockout Mice Fed a Western Diet. Sci Rep 7:193
Sharma, Dana L; Lakhani, Hari Vishal; Klug, Rebecca L et al. (2017) Investigating Molecular Connections of Non-alcoholic Fatty Liver Disease with Associated Pathological Conditions in West Virginia for Biomarker Analysis. J Clin Cell Immunol 8:
Xie, Jeffrey X; Fan, Xiaoming; Drummond, Christopher A et al. (2017) MicroRNA profiling in kidney disease: Plasma versus plasma-derived exosomes. Gene 627:1-8
Haller, Steven T; Kumarasamy, Sivarajan; Folt, David A et al. (2017) Targeted disruption of Cd40 in a genetically hypertensive rat model attenuates renal fibrosis and proteinuria, independent of blood pressure. Kidney Int 91:365-374

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