David Kennedy Lab

David Kennedy, Ph.D. — Lab Research

The devastating diseases of heart failure and renal failure are linked by maladaptation of the body’s ability to handle sodium (salt) and volume (water) loads. Central to this process is an elegant regulatory system composed of effector steroid hormones – known as cardiotonic steroids (CTS) – and their receptor complex, the sodium-potassium adenosine triphosphatase (Na/K ATPase). CTS are ligands of the Na/K-ATPase and production of these hormones are a compensatory mechanism for natriuresis (excretion of sodium in the urine via action on the Na/K-ATPase in the kidney and vascular tone in volume-expanded states such as salt-sensitive hypertension and chronic kidney disease, as well as edematous states like heart failure and pre-eclampsia.

Figure 1 illustrates the balance between the natriuretic effect of cardiotonic steroids (CTS) and the trade-off of inducing Na/K-ATPase-mediated signal transduction leading to cardiac and renal fibrosis.However, CTS also exert “off-target” signal transduction effects beyond their direct effects on the Na/K-ATPase. Hence, chronic stimulation of Na/K-ATPase signaling by CTS has important implications for not only for the natriuretic response to increased salt and water load but also in a “trade-off” pathological adaptation to volume expansion including hypertension, hypertrophy, and fibrosis. One of our laboratory’s major contributions to this field is the clinical and experimental evidence demonstrating the pro-inflammatory and pro-fibrotic pathways initiated by these steroid hormones in both cardiac and renal tissue which make them attractive therapeutic targets for intervention in cardiac and renal disease (Figure 1).

Patients with heart failure and chronic kidney disease often experience progressive cardiac and renal compromise (referred to as “cardio-renal syndrome”) leading to recurrent hospitalizations and clinical deterioration which contemporary therapies of neurohormonal blockade fail to adequately address. As the synthesis and regulation of CTS in volume-expanded states such as heart failure and chronic kidney disease is unknown, developing a fundamental, integrated, and mechanistic understanding of the CTS-Na/K ATPase effector/receptor complex is of critical importance. Thus, the vision and approach of our laboratory’s ongoing and planned research program is to address this critical unmet need as it relates to the synthesis, regulation, translational significance, and therapeutic targets of the CTS-Na/K ATPase axis using a variety of innovative molecular, biochemical, and bioinformatic approaches including systems genetics, targeted genetic and immunologic manipulation of in vitro and in vivo model systems, high performance liquid chromatography and mass spectrometery, as well as advanced, high-content cellular, molecular and physiologic phenotyping.

Last Updated: 3/11/21