Guanosine regulates adenosine levels in the kidney

Abstract

In cell culture, extracellular guanosine increases extracellular adenosine by attenuating the disposition of extracellular adenosine (American Journal of Physiology – Cell Physiology 304: C406–C421, 2013). The goal of this investigation was to determine whether this “guanosine–adenosine mechanism” is operative in an intact organ. Twenty‐seven isolated, perfused mouse kidneys were subjected to metabolic poisons (iodoacetate plus 2,4‐dinitrophenol) to cause energy depletion and thereby stimulate renal adenosine production. Adenosine levels in the renal venous perfusate increased from a baseline of 36 ± 8 to 499 ± 96, 258 ± 50, and 71 ± 13 nmol/L at 15, 30, and 60 min, respectively, after administering metabolic poisons (% of basal; 1366 ± 229, 715 ± 128, and 206 ± 33, respectively). Changes in renal venous levels of guanosine closely mirrored the time course of changes in adenosine: baseline of 15 ± 2 to 157 ± 13, 121 ± 8, and 50 ± 5 nmol/L at 15, 30, and 60 min, respectively (% of basal; 1132 ± 104, 871 ± 59, and 400 ± 51, respectively). Freeze‐clamp experiments in 12 kidneys confirmed that metabolic poisons increased kidney tissue levels of adenosine and guanosine. In eight additional kidneys, we examined the ability of guanosine to reduce the renal clearance of exogenous adenosine; and these experiments revealed that guanosine significantly decreased the renal extraction of adenosine. Because guanosine is metabolized by purine nucleoside phosphorylase (PNPase), in another set of 16 kidneys we examined the effects of 8‐aminoguanine (PNPase inhibitor) on renal venous levels of adenosine and inosine (adenosine metabolite). Kidneys treated with 8‐aminoguanine showed a more robust increase in both adenosine and inosine in response to metabolic poisons. We conclude that in the intact kidney, guanosine regulates adenosine levels.

Guanosine inhibits LPS-induced pro-inflammatory response and oxidative stress in hippocampal astrocytes through the heme oxygenase-1 pathway

“…Furthermore, receptorindependent mechanisms may mediate effects of guanosine. Guanosine has also been shown to increase the extracellular levels of adenosine [28,44]. Although adenosine shows a well-characterized anti-inflammatory effect [55,56], our data showed that adenosine did not prevent TNF-α and IL-1β release in LPS-stimulated astrocytes, in accordance with Kucher and Neary [57].…”

“…Because some effects of guanosine have been shown to be mediated by adenosinergic system [44][45][46], the role of adenosine and/or caffeine (adenosine receptor antagonist) in LPSinduced inflammatory response was also evaluated. Interestingly, adenosine (100 and 1000 μM) did not prevent the increase in cytokine release that occurred after LPS exposure (Table 1).…”

The Guanosine-Adenosine Interaction Exists In Vivo

“…The guanosine-adenosine interaction is so robust that a dose of adenosine that is nontoxic to normal rats kills within a few minutes over 50% of rats pretreated with a dose of guanosine that per se has little effect on the cardiovascular system or kidneys. These findings, particularly when coupled with our in vitro findings in cultured cells and isolated, perfused kidneys (Jackson et al, 2014), leave little doubt that the guanosine-adenosine mechanism is operative and robust.…”

“…To address this question, we recently performed experiments in isolated, perfused mouse kidneys (Jackson et al, 2014). These experiments show that the levels of guanosine and adenosine in the renal venous perfusate and in kidney tissue are highly correlated, that guanosine reduces the renal clearance of exogenous adenosine, and that inhibition of purine nucleoside phosphorylase (PNPase; an enzyme that metabolizes guanosine to guanine) increases the release of both guanosine and adenosine by the kidneys.…”

Simultaneous Inhibition of Glycolysis and Oxidative Phosphorylation Triggers a Multi-Fold Increase in Secretion of Exosomes: Possible Role of 2′,3′-cAMP

“…Nevertheless, by focusing on a potential connection between energy depletion by glucose starvation and exosome release, they provided a rationale for studying IAA/DNP. It has been reported that the combination of IAA and DNP induces a potent reduction of cellular energy charge by simultaneously blocking oxidative phosphorylation and glycolysis 26 . We reasoned that blocking cellular pathways of energy production using IAA and DNP might be an effective strategy for releasing exosomes.…”