Department: Pharmacology, Physiology and Toxicology
Research Cluster: Cardiovascular Disease, Obesity, and Diabetes
Office: BBSC 435-M | Laboratory: BBSC 410
Phone: (304) 696-7359
As an ion pump, the physiological significance of Na/K-ATPase is to maintain essential plasma membrane potential and electrochemical sodium gradient at the expense of ATP. Except functioning as an ion pump, Na/K-ATPase also functions as a signaling transducer through multiple protein–protein interactions. In renal proximal tubules (RPTs), the α1 subunit directly interacts with c-Src kinase via two pairs of domain interactions to form a functional receptor complex, i.e. the Na/K-ATPase/c-Src signaling complex.
Project 1: The Na/K-ATPase signaling and Salt-sensitivity
Recently, we have demonstrated a novel regulatory mechanism that low concentrations of cardiotonic steroids (CTS, specific inhibitors of the Na/K-ATPase) stimulate RPT Na/K-ATPase/c-Src signaling and subsequent redistribution of Na/K-ATPase and sodium/proton exchanger isoform 3 (NHE3). This leads to decreases in RPT sodium reabsorption and thus, increases in sodium excretion to counterbalance sodium retention and related increases of blood pressure. Activation of the Na/K-ATPase signaling (either by cardiotonic steroids, inhibitors of the Na/K-ATPase, or a high salt diet) stimulates total and RPT-mediated fractional urinary sodium excretion. Impairment of this signaling function will cause salt-sensitive hypertension in certain animal models. Our laboratory is interested in studying the molecular mechanism of this phenomenon.
Project 2: Oxidative stress and Na/K-ATPase signaling
Recently, we found that CTS stimulates RPT reactive oxygen species (ROS) generation and ROS can regulate RPT Na/K-ATPase signaling via direct protein carbonylation of amino acid residues of the Na/K-ATPase α1 subunit. We are interested in studying how protein carbonylation regulates the Na/K-ATPase signaling as well as how this regulation is related to cardiotonic steroids and high salt diet mediated changes in renal function.
Project 3: Cardiotonic steroids and renal cardiomyopathy
Cardiotonic steroids signaling through Na/K-ATPase stimulated cardiac and renal fibrosis under certain pathophysiological conditions such as renal insufficiency. This will further worsen renal and cardiac function, leading to severe chronic conditions. We are interested in studying the molecular mechanism(s) in animal models of renal insufficiency.
- Liu J, Kennedy DJ, Yan Y, and Shapiro JI. (2012). Reactive Oxygen Species Modulation of Na/K-ATPase Regulates Fibrosis and Renal Proximal Tubular Sodium Handling. International Journal of Nephrology, 2012:381320. PMID: 22518311 (Review)
- Yan Y, Haller S, Shapiro AP, Malhotra N, Tian J, Xie Z, Malhotra D, and Shapiro JI, Liu J. (2012) Ouabain-Stimulated Trafficking Regulation of the Na/K-ATPase and NHE3 in Renal Proximal Tubule Cells. Mol. Cell. Biochem. 367:175-183. PMID: 22618525
- Gupta S, Yan Y, Malhotra D, Liu J, Xie Z, Najjar SM, Shapiro JI. (2012). Ouabain and insulin induce sodium pump endocytosis in renal epithelium. Hypertension 59(3):665-72. PMID 22311908
- Liu J, Yan Y, Liu L, Xie Z, Malhotra D, Joe B, Shapiro JI. (2011). Impairment of Na/K-ATPase signaling in renal proximal tubule contributes to Dahl salt-sensitive hypertension. J. Biol. Chem,286(26):22806-13. PMID: 21555512
- Liu, J. and Z.J. Xie (2010). The sodium pump and cardiotonic steroids-induced signal transduction protein kinases and calcium-signaling microdomain in regulation of transporter trafficking. Biochimica et Biophysica Acta (BBA) – Molecular Basis of Disease, 2010. 1802(12): p. 1237-45. PMID: 20144708. (Review).
- Cai H, Wu L, Qu W, Malhotra D, Xie Z, Shapiro JI, Liu J. (2008). Regulation of Apical NHE3 Trafficking by Ouabain-Induced Activation of Basolateral Na/K-ATPase Receptor Complex. Am J Physiol Cell Physiol 294, C555-563. PMID18077602
- Liu L, Li J, Liu J, Yuan Z, Pierre SV, Qu W, Zhao X, and Xie Z (2006). Involvement of Na+/K+-ATPase in hydrogen peroxide-induced hypertrophy in cardiac myocytes. Free Radic Biol Med. 2006; 41(10):1548-56
- Liu, J. (2006). Na/K-ATPase Endocytosis Couples Pumping and Leaking Activities in Renal Epithelial Cells: A Hypothesis. Cell Mol Biol (Noisy-le-grand) 52(8): 97-104. PMID: 17535743 (Review)
- Oweis S, Wu L, Kiela PR, Zhao H, Malhotra D, Ghishan FK, Xie Z, Shapiro JI, and Liu J. (2006). Cardiac glycoside downregulates NHE3 activity and expression in LLC-PK1 cells. Am J Physiol Renal Physiol 290: F997-F1008. PMID: 16352745
- Liu, J. (2005). Ouabain-induced endocytosis and signal transduction of the Na/K-ATPase. Frontiers in Bioscience, 10, 2056-2063. PMID; 15970478 (Review)
- Liu J, Liang M, Liu L, Malhotra D, Xie Z, and Shapiro, JI. (2005) Ouabain-induced Endocytosis of the Plasmalemmal Na/K-ATPase in LLC-PK1 Cells Requires Caveolin-1. Kidney Int. 67, 1844-1854. PMID:15840032
- Periyasamy, SM., Liu, J., Tanta, F., Kabak, B., Wakefield, B., Malhotra, D., Kennedy, DJ., Nadoor, A., Fedorova, OV., Gunning, W., Xie, Z., Bagrov, AY., and Shapiro, JI. (2005) Salt Loading Induces Redistribution of the Plasmalemmal Na/K-ATPase in Proximal Tubule Cells. Kidney Int. 67, 1868-1877. PMID: 15840034
- Liu J, Kesiry R, Periyasamy SM, Malhotra D, Xie Z., and Shapiro, JI (2004) Ouabain Induces Endocytosis of Plasmalemmal Na/K-ATPase in LLC-PK1 Cells by a Clathrin-Dependent Mechanism. Kidney Int. 66:227-241. PMID:15200429 (Cover featured)
- Liu, J, Periyasamy SM, Gunning W, Fedorova OV, Bagrov AY, Malhotra D, Xie Z, Shapiro JI.(2002) Effects of cardiac glycosides on sodium pump expression and function in LLC-PK1 and MDCK cells. Kidney Int. 62(6):2118-2125. PMID: 12427136
- Liu, J., Tian, J.; Haas, M.; Shapiro, J.I.; Askari, A.; Xie, Z. (2000) Ouabain interaction with cardiac Na+/K+-ATPase initiates signal cascades independent of changes in intracellular Na+ and Ca2+. J. Biol. Chem. 275, 27838-27844. PMID: 10874029
- Xie, Z., Kometiani, P., Liu, J., Li, J., Shapiro, J.I., And Askari, A. (1999) Intracellular Reactive Oxygen Species Mediate the Linkage of Na+/K+-ATPase to Hypertrophy and Its Marker Genes in Cardiac Myocytes. J. Biol. Chem, 274(27):19323-19328. PMID: 10383443