My research has focused on the roles of endogenous cardiotonic steroids, oxidative stress and Na/K-ATPase signaling transduction on renal sodium handling, salt-sensitive hypertension as well as renal/cardiac fibrosis and organ remodeling. Recently, we demonstrated that cardiotonic steroids signaling through the Na/K-ATPase generated ROS is essential for the overall Na/K-ATPase signal transduction, as well as that the Na/K-ATPase α1 subunit and c-Src form a signaling complex under native resting condition. We have also demonstrated the relevance of the Na/K-ATPase signaling mediated oxidant amplification loop to the pathophysiology of renal and cardiovascular diseases and salt sensitivity.
Cardiotonic steroids and the Na/K-ATPase signaling: This part of research focuses demonstrated that cardiotonic steroids (also known as endogenous digitalis-like substances such as ouabain) mediated Na/K-ATPase signaling pathways in cardiomyocytes and renal proximal tubular cells. My work, along with others, demonstrated that the Na/K-ATPase functions not only as a classic “ion pump” but also as a “signaling pump”. The signaling function of the Na/K-ATPase is independent of changes in intracellular Na+ concentration and is regulated by protein-protein interactions.
The Na/K-ATPase signaling and salt-sensitivity: This part of research demonstrated that the Na/K-ATPase signaling mediated endocytosis of the Na/K-ATPase and sodium/hydrogen exchanger isoform 3 (NHE3) is strongly implicated as causative of experimental Dahl salt-sensitive hypertension. Specifically, cardiotonic steroids and/or reactive oxygen species (ROS), signaling through Na/K-ATPase, stimulate coordinated redistribution of Na/K-ATPase and NHE3 in renal proximal tubule, leading to stimulation of total and fractional sodium excretion.
ROS and the Na/K-ATPase signaling: This part of research demonstrated that ROS is required and involved in the Na/K-ATPase signaling in a feed-forward mechanism. Two amino acid residues were identified that undergo direct protein carbonylation modification which is critical to the Na/K-ATPase signaling.
The Na/K-ATPase signaling and renal/cardiac fibrosis: This part of research demonstrated that cardiotonic steroids and ROS mediated Na/K-ATPase signaling causes fibrosis and organ remodeling of kidney and heart, in our rat and mouse 5/6 partial nephrectomy (PNx) models. These effects were significantly attenuated by administration of antibodies against cardiotonic steroids, an active peptide blocking Na/K-ATPase signaling and other manipulations. We also identify a Na/K-ATPase signaling mediated oxidant amplification loop in the processes.