Adenosine receptors and signaling in the kidney.

Abstract

It is now generally accepted that adenosine is capable of regulating a wide range of physiological functions. Nowhere is the diversity of this action better illustrated than in the kidney. When adenosine binds to plasma membrane receptors on a variety of cell types in the kidney, it stimulates functional responses that span the entire spectrum of renal physiology, including alterations in hemodynamics, hormone and neurotransmitter release, and tubular reabsorption. These responses to adenosine appear to represent a means by which the organ and its constituent cell types can regulate their metabolic demand such that it is maintained at an appropriate level for the prevailing metabolic supply. Extracellular adenosine, produced from the hydrolysis of adenosine 5'-monophosphate and stimulated by increased substrate availability and enzyme induction, acts on at least two types of cell surface receptors to stimulate or inhibit the production of cyclic adenosine-3',5'-monophosphate and also acts in some renal cells to stimulate the production of inositol phosphates and elevation of cytosolic calcium concentration. To understand when and why this complicated system becomes activated, how it interacts with other known extracellular effector systems, and ultimately how to manipulate the system to therapeutic advantage by selective agonists or antagonists, requires a detailed knowledge of renal adenosine receptors and their signaling mechanisms. The following discussion attempts to highlight our knowledge in this area, to present a modified hypothesis for adenosine as a feedback regulator of renal function, and to identify some important questions regarding the specific cellular mechanisms of adenosine in renal cell types. T he kidney, like many organs, is endowed with intrinsic mechanisms that allow it to self-regulate many of its functions. Two well-known examples are the relatively constant glomerular filtration rate (GFR) and renal blood flow over a wide range of arterial pressure (i.e., autoregulation) and the ability to release renin in response to changes in renal perfusion pressure independent of neural or humoral signals. It was the search to understand the renal mechanism responsible for this intrinsic regulation that prompted investigators to turn their interest toward adenosine. Previous reviews 1 -5 have dealt specifically with a proposed role for adenosine in the control of GFR and renin release. Although this may have prompted much of the original interest in intrarenal adenosine, recent investigations have revealed adenosine to have a much broader regulatory role. The present discussion focuses From the Departments of Physiology and Biochemistry, Michigan State University, East Lansing, Mich.

Novel therapeutics acting via purine receptors

“…Consistently, adenosine analogs stimulate active sodium transport in toad kidney cells [47]. Moreover, binding studies and studies of adenylate cyclase activity demonstrate the presence of both A 1 and A 2 -adenosine receptors [48].…”

Acute Regulation of Na/H Exchanger NHE3 by Adenosine A1 Receptors Is Mediated by Calcineurin Homologous Protein

“…Adenosine modulates many functions in mammals via binding to A 1 , A 2A , A 2B , and/or A 3 adenosine receptors (1,3). In the kidney, adenosine regulates glomerular filtration rate, renin release, erythropoietin production, cellular proliferation, and tubular water and Na ϩ transport (2,4). Renal adenosine generation is markedly increased in response to hypoxia, ischemia, or inflammation (2,3).…”

Bimodal Acute Effects of A1 Adenosine Receptor Activation on Na+/H+ Exchanger 3 in Opossum Kidney Cells

“…Of the four adenosine receptors that have been cloned, A 1 , A 2A , and A 3 adenosine receptors are known to participate in renal physiology (1)(2)(3)(4)(5)(6)(7). Regarding signal transduction, A 1 and A 3 adenosine receptors are positively linked to the phospholipase C (PLC) effector system and negatively coupled to the cAMP/protein kinase A effector system, whereas A 2A receptors stimulate adenylate cyclase and cAMP formation but may also activate alternative signaling pathways (1,8).…”

“…Recently, evidence has been accumulating that A 1 and A 2A adenosine receptor agonists in addition to modulating renal blood flow, renin release, and tubular transport (1,5,7) may have potent effects in protecting renal tissue against ischemic reperfusion injury (1,6). In kidneys subjected to ischemiareperfusion injury, preischemic administration of A 1 adenosine receptor agonists induced ischemic preconditioning, whereas postischemic A 2A adenosine receptor activation reduced tissue injury by attenuating the reperfusion phase of the injury process (6,9,10).…”