Diuretics are used as a pharmacological therapeutic intervention in diseases including hypertension, heart failure, liver dysfunction and chronic kidney disease. These disease states are associated with increased renal sympathetic tone, which in turn, ultimately leads to decreases in both renal blood flows (RBF) and glomerular filtration rate (GFR). Unfortunately, diuretic treatment has been shown to also increase renal sympathetic tone thus adding to the observed deleterious effects on kidney hemodynamics already present in these patients. This effect could be a contributing mechanism underlying the conditions of diuretic resistance and intolerance which limit the therapeutic potential of the current diuretics. To address this significant public health issue, effort is being put forth to develop new diuretic drugs suitable for chronic treatment that preserve renal hemodynamics. Observations from our laboratory demonstrate that BG9928, a selective A1 adenosine receptor (A1AR) antagonist, reduces renal sympathetic nerve stimulation (RSNS)-induced renal vasoconstriction. These findings suggest that A1AR activation in the renal neuroeffector junction potentiates renal sympathetic neurotransmission. RSNS has been shown to increase the concentration of norepinephrine (NE) and ATP (also the enzymes that metabolize ATP to adenosine) in the neuroeffector junction. Since the precise role that adenosine plays in modulating renal sympathetic neurotransmission remains undefined, our overall objective is to examine the mechanism by which adenosine enhances the vasoconstrictive response to RSNS. In conjunction, we will demonstrate the means by which selective A1AR antagonists exert their diuretic effects while preserving favorable renal hemodynamics. Since pre-junctional A1ARs are inhibitory, we suggest here that it is the post-junctional A1ARs that are the predominant site of action of adenosine in response to RSNS. Also propose that adenosine potentiates NE's vasoconstrictive actions via coincident signaling (convergence of pathways). To test our hypothesis, we will use multiple approaches/techniques providing considerable training potential for this fellowship application. 1) We will demonstrate that antagonism of only the A1AR subtype will reduce RSNS-induced vasoconstriction in the presence of released NE. 2) We will show using A1AR knock-out animals that reconstitution of only the post-junction receptors restores the wild-type response to RSNS. 3) Using isolated kidneys and in vitro experiments, we will demonstrate the precise mechanism of coincident signaling between adenosine and NE that increases the vasoconstrictive response to RSNS. The completion of this project, in addition to the significant training potential, will identify a previously unappreciated mechanism for adenosine in regulating renal hemodynamics and support for the use of A1AR antagonists in conditions with elevated renal sympathetic tone. The information obtained from these experiments will be of interest to a broad audience, ranging from basic scientists studying renal physiology to clinical physicians evaluating potential therapeutic benefit and/or complications of diuretic treatment.

Public Health Relevance

The long-term use of diuretics as a therapeutic intervention for diseases of the heart, liver and kidney represents a significant concern for public health. The current classes of diuretics, although relatively effective in short-term disease management, possess undesired side effects thus limiting their therapeutic potential. This fellowship grant application examines the role of the endogenous molecule adenosine in modulating renal sympathetic neurotransmission and will elucidate the mechanism of action of an emerging class of diuretics that target adenosine-mediated signaling in the kidney.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZDK1-GRB-G (M1))
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Rankin, Tracy L
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University of Pittsburgh
Schools of Medicine
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Jackson, Edwin K; Cheng, Dongmei; Mi, Zaichuan et al. (2012) Role of A1 receptors in renal sympathetic neurotransmission in the mouse kidney. Am J Physiol Renal Physiol 303:F1000-5