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.
We have discovered a new receptor mechanism that plays an important role in the pathogenesis of renal and cardiac diseases. The proposed research will further advance our understanding of this receptor mechanism and explore the possibility of using the newly discovered receptor antagonists to prevent renal insufficiency and high salt diet-induced cardiac lesions.
|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|
|Srikanthan, Krithika; Shapiro, Joseph I; Sodhi, Komal (2016) The Role of Na/K-ATPase Signaling in Oxidative Stress Related to Obesity and Cardiovascular Disease. Molecules 21:|
|Srikanthan, Krithika; Feyh, Andrew; Visweshwar, Haresh et al. (2016) Systematic Review of Metabolic Syndrome Biomarkers: A Panel for Early Detection, Management, and Risk Stratification in the West Virginian Population. Int J Med Sci 13:25-38|
|Sodhi, Komal; Bracero, Lucas; Feyh, Andrew et al. (2016) Role of Serum Biomarkers in Early Detection of Non-Alcoholic Steatohepatitis and Fibrosis in West Virginian Children. J Clin Cell Immunol 7:|
|Peterson, Stephen J; Vanella, Luca; Gotlinger, Katherine et al. (2016) Oxidized HDL is a potent inducer of adipogenesis and causes activation of the Ang-II and 20-HETE systems in human obese females. Prostaglandins Other Lipid Mediat 123:68-77|
|Argyropoulos, Christos; Rondon-Berrios, Helbert; Raj, Dominic S et al. (2016) Hypertonicity: Pathophysiologic Concept and Experimental Studies. Cureus 8:e596|
|Sodhi, Komal; Hilgefort, Jordan; Banks, George et al. (2016) Uric Acid-Induced Adipocyte Dysfunction Is Attenuated by HO-1 Upregulation: Potential Role of Antioxidant Therapy to Target Obesity. Stem Cells Int 2016:8197325|
|Haller, Steven T; Yan, Yanling; Drummond, Christopher A et al. (2016) Rapamycin Attenuates Cardiac Fibrosis in Experimental Uremic Cardiomyopathy by Reducing Marinobufagenin Levels and Inhibiting Downstream Pro-Fibrotic Signaling. J Am Heart Assoc 5:|
|Murphy, Timothy P; Cooper, Christopher J; Pencina, Karol M et al. (2016) Relationship of Albuminuria and Renal Artery Stent Outcomes: Results From the CORAL Randomized Clinical Trial (Cardiovascular Outcomes With Renal Artery Lesions). Hypertension 68:1145-1152|
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