Cutting Edge: A2B Adenosine Receptor Signaling Provides Potent Protection during Intestinal Ischemia/Reperfusion Injury

Abstract

Gastrointestinal ischemia/reperfusion (IR) injury significantly contributes to the morbidity and mortality of critical illness. In this study, we hypothesized a protective role for extracellular adenosine signaling in intestinal IR injury. Initial profiling studies of mucosal scrapings following murine IR demonstrated selective induction of the A2B adenosine receptor (A2BAR) transcript. Moreover, genetargeted mice for the A2BAR showed more profound intestinal IR injury compared with controls. In contrast, A2AAR؊/؊ mice exhibited no differences in intestinal injury compared with littermate controls. In addition, selective inhibition of the A2BAR resulted in enhanced intestinal inflammation and injury during IR. Furthermore, A2BAR agonist treatment (BAY 60-6583) protected from intestinal injury, inflammation, and permeability dysfunction in wild-type mice, whereas the therapeutic effects of BAY 60-6583 were abolished following targeted A2BAR gene deletion. Taken together, these studies demonstrate the A2BAR as a novel therapeutic target for protection during gastrointestinal IR injury.

CD73-Dependent Generation of Adenosine and Endothelial Adora2b Signaling Attenuate Diabetic Nephropathy

“…As first step, we induced diabetic nephropathy in previously described Adora2b 2/2 mice. 23,[28][29][30][31][48][49][50][51] Similar to the preceding studies in Cd73 2/2 mice, we observed a more severe degree of diabetic nephropathy in Adora2b 2/2 mice without differences regarding systolic BP and blood glucose levels (Supplemental Figure 4, A and B), but a more severe degree of body weight loss ( Figure 5A), increased kidney weight (Figure 5B), and elevated urine (Figure 5C) and drinking ( Figure 5D) volumes. Determination of the GFR showed a more severe hyperfiltration in Adora2b 2/2 mice compared with diabetic control mice ( Figure 5E).…”

“…9,18,20 Once generated into the extracellular compartment, adenosine can signal through four distinct adenosine receptors (Adora1, Adora2a, Adora2b, or Adora3). Previous studies had implicated CD73-dependent generation of extracellular adenosine and concomitant adenosine signaling in tissue protection during conditions of acute tissue injury, such as AKI, [21][22][23][24][25][26] hepatic 10,20,27 or intestinal 17,18,28 ischemia, or myocardial infarction. 10,[29][30][31][32] In contrast, the functional role of extracellular adenosine generation and signaling during chronic disease states is less clear.…”

Volatile Anesthetics and AKI

“…[65][66][67][68] Indeed, CD73 activation and adenosine generation protect against renal, intestinal, and cardiac IR injury by reducing necrosis and inflammation. [69][70][71] In particular, renal tubular A 1 AR activation reduces necrosis and apoptosis, whereas A 2a AR stimulation leads to tissue protection by attenuating leukocyte-mediated inflammation after renal IR. Renal A 1 ARs dramatically reduce proximal tubular necrosis and apoptosis via activation of extracellular signal-regulated kinase, Akt, and heat shock protein 27 through a pertussis toxin-sensitive G protein pathway.…”

Adenosine Generation and Signaling during Acute Kidney Injury

“…24,23,25 As such, extracellular adenosine production is enhanced during limited oxygen availability 23,26 -29 and is critical to maintaining cellular functions during hypoxia, 30,23,31 or to dampen hypoxia-driven inflammation. [32][33][34]28,17 On the basis of such findings, recent studies in the kidneys implicate extracellular adenosine generation and signaling as pharmacologic targets for protection from ischemia.…”