Lack of effect of extracellular adenosine generation and signaling on renal erythropoietin secretion during hypoxia

Grenz, Almut; Zhang, Hua; Weingart, J B; Wietersheim, Simone von; Eckle, Tobias; Schnermann, Jürgen; Köhle, Christoph; Kloor, Doris; Gleiter, Christoph H.; Vallon, Volker; Eltzschig, Holger K.; Oßwald, Hartmut

doi:10.1152/ajprenal.00243.2007

Cited by 26 publications

(19 citation statements)

References 52 publications

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“…Therefore, it can be expected that hyperhomocysteinemia (HHcy) induced an accumulation of AdoHcy resulting in a decreased MP which may lead to an impaired EPO production following CO exposure. In the first series of experiments we established a dose-response curve of CO mediated increases of EPO plasma concentration in anesthetized rats confirming data from the literature obtained in conscious animals [32]. The infusion of Hcy induced a moderate (low dose) and a severe (high dose) HHcy resulting in a 2-3 fold increase of AdoHcy tissue content.…”

Section: Discussionsupporting

confidence: 83%

Hyperhomocysteinemia is Associated with Decreased Erythropoietin Expression in Rats

Grenz

Hermes

Hammel

et al. 2010

Cell Physiol Biochem

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Background/Aims: Elevated plasma homocysteine (Hcy) levels have been identified as a pathogenic factor causing a variety of pathological changes in different cells and tissues. In vertebrates, Hcy is produced solely from S-adenosylhomocysteine (AdoHcy) through the catalysis of AdoHcy-hydrolase. The direction of AdoHcy-hydrolase activity is determined by its cytosolic substrate concentrations, thereby controlling intracellular AdoHcy levels. Most S-adenosylmethionine (AdoMet)-dependent methyltransferases are regulated in vivo by the ratio of AdoMet/AdoHcy, which is termed “methylation potential” (MP). To test whether high rates of erythropoietin (EPO) expression is reduced by a low MP in vivo we choosed the model of increased EPO production following carbon monoxide (CO) exposure in rats in which high transcriptional activity is responsible for renal EPO production. Results: To induce a sustained hyperhomocysteinemia in rats, we infused i.v. a low or high dose of Hcy resulting in Hcy plasma levels of 87.4±6.2 and 300.8±23.7 µmol/l, respectively. Renal tissue contents of AdoHcy, AdoMet, and adenosine (Ado) were measured after freeze clamp by means of HPLC. Within 4h of CO exposure EPO serum levels increased from 13.6±0.4 (control) to 2254.8±278.3 mIU/ml. Only high dose of Hcy reduces both, the MP from 40.8±2.0 to 8.2±1.0 in the kidney as well as EPO serum levels by 40% compared to control rats. Conclusion: Our data show that severe hyperhomocysteinemia (HHcy) affects the MP in the renal tissue and lowers EPO expression following CO induced intoxication. This result supports the concept that efficient EPO production requires an unimpaired MP.

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Section: Discussionsupporting

confidence: 83%

Hyperhomocysteinemia is Associated with Decreased Erythropoietin Expression in Rats

Grenz

Hermes

Hammel

et al. 2010

Cell Physiol Biochem

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“…Beginning 1 day prior to infection, WT mice were treated daily with 1 mg/kg of the specific A 1 -AdoR antagonist DPCPX (Tocris Bioscience, Ellisville, MO) by i.p. injection in 100 l saline (30). Controls received an equal volume of the vehicle.…”

Section: Methodsmentioning

confidence: 99%

Activation of A ₁ -Adenosine Receptors Promotes Leukocyte Recruitment to the Lung and Attenuates Acute Lung Injury in Mice Infected with Influenza A/WSN/33 (H1N1) Virus

Aeffner

Woods

Davis

2014

J Virol

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We have shown that bronchoalveolar epithelial A 1 -adenosine receptors (A 1 -AdoR) are activated in influenza A virus-infected mice. Alveolar macrophages and neutrophils also express A 1 -AdoRs, and we hypothesized that activation of A 1 -AdoRs on these cells will promote macrophage and neutrophil chemotaxis and activation and thereby play a role in the pathogenesis of influenza virus-induced acute lung injury. Wild-type (WT) C57BL/6 mice, congenic A 1 -AdoR knockout (A 1 -KO) mice, and mice that had undergone reciprocal bone marrow transfer were inoculated intranasally with 10,000 PFU/mouse influenza A/WSN/33 (H1N1) virus. Alternatively, WT mice underwent daily treatment with the A 1 -AdoR antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) from 1 day prior to inoculation. Infection increased bronchoalveolar lining fluid (BALF) adenosine comparably in WT and A 1 -KO mice. Infection of WT mice resulted in reduced carotid arterial O 2 saturation (hypoxemia), lung pathology, pulmonary edema, reduced lung compliance, increased basal airway resistance, and hyperresponsiveness to methacholine. These effects were absent or significantly attenuated in A 1 -KO mice. Levels of BALF leukocytes, gamma interferon (IFN-␥), and interleukin 10 (IL-10) were significantly reduced in infected A 1 -KO mice, but levels of KC, IP-10, and MCP-1 were increased. Reciprocal bone marrow transfer resulted in WT-like lung injury severity, but BALF leukocyte levels increased only in WT and A 1 -KO mice with WT bone barrow. Hypoxemia, pulmonary edema, and levels of BALF alveolar macrophages, neutrophils, IFN-␥, and IL-10 were reduced in DPCPX-treated WT mice. Levels of viral replication did not differ between mouse strains or treatment groups. These findings indicate that adenosine activation of leukocyte A 1 -AdoRs plays a significant role in their recruitment to the infected lung and contributes to influenza pathogenesis. A 1 -AdoR inhibitor therapy may therefore be beneficial in patients with influenza virus-induced lung injury. IMPORTANCEBecause antiviral drugs are of limited efficacy in patients hospitalized for influenza virus-induced respiratory failure, there is an urgent need for new therapeutics that can limit the progression of lung injury and reduce influenza death rates. We show that influenza A virus infection results in increased production of the nucleoside adenosine in the mouse lung and that activation of A 1 -subtype adenosine receptors by adenosine contributes significantly to both recruitment of innate immune cells to the lung and development of acute lung injury following influenza virus infection. We also show that treatment with an A 1 -adenosine receptor antagonist reduces the severity of lung injury in influenza virus-infected mice. Our findings indicate that adenosine plays an important and previously unrecognized role in the innate immune response to influenza virus infection and suggest that drugs which can inhibit either generation of adenosine or activation of A 1 -adenosine receptors may be beneficia...

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“…Intracellular adenosine may be re-phosphorylated to AMP by the activity of adenosine kinase. Extracellular adenosine concentration is largely reduced in mice lacking CD73, suggesting that degradation of adenine nucleotides is responsible for the production of extracellular adenosine (20, 21). In contrast, inhibitors of ADA and nucleoside transporters increased extracellular adenosine, suggesting the importance of these pathways in the removal of extracellular adenosine (22, 23).…”

Section: Where Extracellular Adenosine Comes Frommentioning

confidence: 99%

Extracellular Adenosine-Mediated Modulation of Regulatory T Cells

2014

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Extracellular adenosine-dependent suppression and redirection of pro-inflammatory activities are mediated by the signaling through adenosine receptors on the surface of most immune cells. The immunosuppression by endogenously-produced adenosine is pathophysiologically significant since inactivation of A2A/A2B adenosine receptor (A2AR/A2BR) and adenosine-producing ecto-enzymes CD39/CD73 results in the higher intensity of immune response and exaggeration of inflammatory damage. Regulatory T cells (Treg) can generate extracellular adenosine, which is implicated in the immunoregulatory activity of Tregs. Interestingly, adenosine has been shown to increase the numbers of Tregs and further promotes their immunoregulatory activity. A2AR-deficiency in Tregs reduces their immunosuppressive efficacy in vivo. Thus, adenosine is not only directly and instantly inhibiting to the immune response through interaction with A2AR/A2BR on the effector cells, but also adenosine signaling can recruit other immunoregulatory mechanisms, including Tregs. Such interaction between adenosine and Tregs suggests the presence of a positive feedback mechanism, which further promotes negative regulation of immune system through the establishment of immunosuppressive microenvironment.

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Lack of effect of extracellular adenosine generation and signaling on renal erythropoietin secretion during hypoxia

Cited by 26 publications

References 52 publications

Hyperhomocysteinemia is Associated with Decreased Erythropoietin Expression in Rats

Hyperhomocysteinemia is Associated with Decreased Erythropoietin Expression in Rats

Activation of A ₁ -Adenosine Receptors Promotes Leukocyte Recruitment to the Lung and Attenuates Acute Lung Injury in Mice Infected with Influenza A/WSN/33 (H1N1) Virus

Extracellular Adenosine-Mediated Modulation of Regulatory T Cells

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Lack of effect of extracellular adenosine generation and signaling on renal erythropoietin secretion during hypoxia

Cited by 26 publications

References 52 publications

Hyperhomocysteinemia is Associated with Decreased Erythropoietin Expression in Rats

Hyperhomocysteinemia is Associated with Decreased Erythropoietin Expression in Rats

Activation of A 1 -Adenosine Receptors Promotes Leukocyte Recruitment to the Lung and Attenuates Acute Lung Injury in Mice Infected with Influenza A/WSN/33 (H1N1) Virus

Extracellular Adenosine-Mediated Modulation of Regulatory T Cells

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Product

Resources

About

Activation of A ₁ -Adenosine Receptors Promotes Leukocyte Recruitment to the Lung and Attenuates Acute Lung Injury in Mice Infected with Influenza A/WSN/33 (H1N1) Virus