Contribution of Adenosine A2B Receptors to Inflammatory Parameters of Experimental Colitis

Frick, Julia-Stefanie; MacManus, Christopher F.; Scully, Melanie; Glover, Louise; Eltzschig, Holger K.; Colgan, Sean P.

doi:10.4049/jimmunol.0801324

Cited by 144 publications

(179 citation statements)

References 52 publications

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“…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).…”

Section: Diabetic Nephropathy Is More Severe In Adora2bsupporting

confidence: 74%

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

Tak¹,

Ridyard²,

Kim

et al. 2014

Journal of the American Society of Nephrology

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Nucleotide phosphohydrolysis by the ecto-59-nucleotidase (CD73) is the main source for extracellular generation of adenosine. Extracellular adenosine subsequently signals through four distinct adenosine A receptors (Adora1, Adora2a, Adora2b, or Adora3). Here, we hypothesized a functional role for CD73-dependent generation and concomitant signaling of extracellular adenosine during diabetic nephropathy. CD73 transcript and protein levels were elevated in the kidneys of diabetic mice. Genetic deletion of CD73 was associated with more severe diabetic nephropathy, whereas treatment with soluble nucleotidase was therapeutic. Transcript levels of renal adenosine receptors showed a selective induction of Adora2b during diabetic nephropathy. In a transgenic reporter mouse, Adora2b expression localized to the vasculature and increased after treatment with streptozotocin. Adora2b 2/2 mice experienced more severe diabetic nephropathy, and studies in mice with tissue-specific deletion of Adora2b in tubular epithelia or vascular endothelia implicated endothelial Adora2b signaling in protection from diabetic nephropathy. Finally, treatment with a selective Adora2b agonist (BAY 60-6583) conveyed potent protection from diabetes-associated kidney disease. Taken together, these findings implicate CD73-dependent production of extracellular adenosine and endothelial Adora2b signaling in kidney protection during diabetic nephropathy.

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Section: Diabetic Nephropathy Is More Severe In Adora2bsupporting

confidence: 74%

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

Tak¹,

Ridyard²,

Kim

et al. 2014

Journal of the American Society of Nephrology

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“…Interestingly, other investigators have demonstrated more of an anti-inflammatory and protective role for A 2B AR receptors in ischemia-reperfusion injury (16,17) and murine colitis (13). Differences in experimental protocols, animal strains, and environmental conditions have been proposed as possible reasons for the discrepancies in the findings (13).…”

Section: Resultsmentioning

confidence: 99%

“…In the study, we found that upregulation of A 2B ARs occurs in TcdA-or TcdB-challenged human intestinal epithelial cells. Others have shown that both A 2A AR and A 2B AR are expressed during dextran sodium sulfate (DSS)-induced colitis (13), while A 2B AR is selectively induced in ischemia-reperfusion injury in mice (17). A 2A AR mRNA is not as prominently expressed as A 2B AR in epithelial cells; A 2A AR may be more localized in immune rather than epithelial cells in the intestinal tract (12,18).…”

Section: Resultsmentioning

confidence: 99%

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Contribution of Adenosine A _2B Receptors in Clostridium difficile Intoxication and Infection

Warren

Calabrese

et al. 2012

Infect Immun

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A denosine receptors-A 1 , A 2A , A 2B , and A 3 -are G proteincoupled receptors expressed in a wide variety of tissues. A 2B adenosine receptors (A 2B ARs) are the predominant adenosine receptors in intestinal epithelial cells and are increased in the presence of inflammation (36). A 2B AR mRNA had been shown to be upregulated in the presence of colitis in both murine and human tissues (23). Adenosine, through its activity on A 2B AR, mediates chloride secretion (4, 23, 36) and secretion of inflammatory cytokines, interleukin-6 (IL-6), and keratinocyte-derived chemokine (KC) (33). In murine models of inflammatory bowel disease (IBD), the effects of blocking or deleting A 2B ARs have been inconsistent. Reduced tissue levels of inflammatory mediators, clinical disease activity score, and histopathology were reported by Kolachala et al. (24,25), while increased pathology was reported by Frick et al. (13).Clostridium difficile infection (CDI) induces a pronounced systemic and intestinal inflammatory response. Intestinal disease is induced by large clostridial toxins A (TcdA) and B (TcdB) (39). These toxins glucosylate the small G protein family of Rho, Rac, and Cdc42 leading to actin depolymerization, cytoskeleton disruption, and intestinal barrier dysfunction (20,21). Although the exact mechanisms involved are still unclear, infiltration of inflammatory cells and secretion of proinflammatory mediators occur (32). Inflammatory diarrhea ensues, and a systemic inflammatory response is observed in severe cases. Severe infection presents as pseudomembranous colitis, toxic megacolon, severe sepsis, or septic shock. Although primarily considered antibiotic-precipitated disease, treatment of CDI still relies on antimicrobial agents active against C. difficile. Unfortunately, antimicrobial therapy is associated with recurrent disease in 20% of the initial cases, with increasing recurrence with increasing numbers of prior CDIs (22). Treatment of severe disease and recurrences is challenging.This study aims to determine whether A 2B ARs are involved in C. difficile toxin-induced intestinal injury, secretion, and inflammation. Furthermore, we examine the effects of inhibition of A 2B AR activity during CDI in the mouse model of the disease.(This study was partially presented at the 48th Annual Meeting of the Infectious Disease Society of America, Vancouver, Canada, 21 to 24 October 2010.) MATERIALS AND METHODSAdenosine receptor subtype assay. Adenosine receptor subtype (A 1 , A 2A , A 2B , and A 3 ) mRNAs were assayed by quantitative PCR (qPCR) in a human colonic cell line, HCT-8, with or without TcdA or TcdB. (Toxins were kindly provided by David Lyerly.) HCT-8 cells were grown in filtered RPMI 1640 medium in the presence of 10% fetal bovine serum, 1 mM sodium pyruvate, and 0.1 U of Pen Strep (penicillin-streptomycin; Gibco catalog no. 15140) in 5% CO 2 at 37°C. A 96-well plate was seeded with trypsin-EDTA-dissociated cells in 200 l of the medium. Upon 80% confluence, the cells were treated with TcdA (0.01, 0.1, 1, 10, and 1...

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“…Adora2b signaling, we next performed studies to identify the role of Adora2b expressed on different cell types. As previous studies had implicated Adora2b signaling on endothelia (32) or epithelia (33) in organ inflammation, we used a transgenic mouse line with a floxed Adora2b gene (34) . Indeed, mice with genetic deletion of the Adora2b in tubular epithelia retained dipyridamole-mediated kidney protection from ischemia, indicating that ENT inhibition-mediated kidney protection is independent of Adora2b expression on tubular epithelia ( Figure 9, A-E).…”

Section: Figurementioning

confidence: 99%

Equilibrative nucleoside transporter 1 (ENT1) regulates postischemic blood flow during acute kidney injury in mice

Grenz¹,

Bauerle²,

Dalton³

et al. 2017

Journal of Clinical Investigation

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A complex biologic network regulates kidney perfusion under physiologic conditions. This system is profoundly perturbed following renal ischemia, a leading cause of acute kidney injury (AKI) -a life-threatening condition that frequently complicates the care of hospitalized patients. Therapeutic approaches to prevent and treat AKI are extremely limited. Better understanding of the molecular pathways promoting postischemic reflow could provide new candidate targets for AKI therapeutics. Due to its role in adapting tissues to hypoxia, we hypothesized that extracellular adenosine has a regulatory function in the postischemic control of renal perfusion. Consistent with the notion that equilibrative nucleoside transporters (ENTs) terminate adenosine signaling, we observed that pharmacologic ENT inhibition in mice elevated renal adenosine levels and dampened AKI. Deletion of the ENTs resulted in selective protection in Ent1 -/-mice. Comprehensive examination of adenosine receptor-knockout mice exposed to AKI demonstrated that renal protection by ENT inhibitors involves the A2B adenosine receptor. Indeed, crosstalk between renal Ent1 and Adora2b expressed on vascular endothelia effectively prevented a postischemic no-reflow phenomenon. These studies identify ENT1 and adenosine receptors as key to the process of reestablishing renal perfusion following ischemic AKI. If translatable from mice to humans, these data have important therapeutic implications. IntroductionAcute kidney injury (AKI) is clinically defined by an abrupt reduction in kidney function (e.g., a decrease in glomerular filtration rate [GFR]), occurring over a period of minutes to days. AKI is frequently caused by an obstruction of renal blood flow (renal ischemia) and represents an important cause of morbidity and mortality of patients (1-3). Indeed, a recent study revealed that only a mild increase (0.3 mg/dl) in the serum creatinine level is associated with a 70% greater risk of death than in patients without this increase (2, 3). Particularly for surgical patients, AKI represents a significant threat. For example, surgical procedures requiring cross-clamping of the aorta and renal vessels are associated with a rate of AKI of up to 30% (4). Similarly, AKI after cardiac surgery occurs in up to 10% of patients under normal circumstances and is associated with dramatic increases in mortality (5). In addition, patients with sepsis frequently go on to develop AKI, and the combination of moder-

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Contribution of Adenosine A2B Receptors to Inflammatory Parameters of Experimental Colitis

Cited by 144 publications

References 52 publications

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

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

Contribution of Adenosine A _2B Receptors in Clostridium difficile Intoxication and Infection

Equilibrative nucleoside transporter 1 (ENT1) regulates postischemic blood flow during acute kidney injury in mice

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Contribution of Adenosine A2B Receptors to Inflammatory Parameters of Experimental Colitis

Cited by 144 publications

References 52 publications

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

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

Contribution of Adenosine A 2B Receptors in Clostridium difficile Intoxication and Infection

Equilibrative nucleoside transporter 1 (ENT1) regulates postischemic blood flow during acute kidney injury in mice

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Contribution of Adenosine A _2B Receptors in Clostridium difficile Intoxication and Infection