Protective Role of Ecto-5′-Nucleotidase (CD73) in Renal Ischemia

Grenz, Almut; Zhang, Hua; Eckle, Tobias; Mittelbronn, Michel; Wehrmann, Manfred; Köhle, Christoph; Kloor, Doris; Thompson, Linda F.; Oßwald, Hartmut; Eltzschig, Holger K.

doi:10.1681/asn.2006101141

Cited by 144 publications

(159 citation statements)

References 37 publications

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“…Although the lymph was derived from patients with different underlying morbidities, these data thus collectively suggest that the intralymphatic lymphocytes can produce substantial levels of anti-inflammatory adenosine when they are exiting the tissues. CD73 regulates the permeability of blood vessels under inflammatory conditions [7,[11][12][13][14][15][16][17]30]. Thus, the blood vasculature of all studied organs in CD73-deficient mice has been shown to be leakier to small molecules in multiple models of ischemiareperfusion injury and LPS-induced inflammation when compared to WT mice.…”

Section: Discussionmentioning

confidence: 99%

“…It is synthesized both on blood ECs (BECs) and lymphatic ECs (LECs). The role of CD73 on BECs in controlling vascular permeability and leukocyte trafficking is relatively well understood [11][12][13][14][15][16][17], but the function of lymphatic CD73 remains completely enigmatic. In terms of lymphatic CD73, it is only known that the molecule is expressed on afferent, but not on efferent, LECs, that the expression is higher on LEC than BEC and also that CD73 on LECs is not involved in lymphocyte or DC homing from the periphery into the draining lymph node [18].…”

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confidence: 99%

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Ecto‐5′‐nucleotidase/CD73 enhances endothelial barrier function and sprouting in blood but not lymphatic vasculature

et al. 2014

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CD73/ecto-5 -nucleotidase is a key enzyme in the regulation of purinergic signaling and inflammatory reactions. It hydrolyzes extracellular AMP into adenosine, which dampens immune cell activation, and reduces leukocyte trafficking. By comparing CD73 expression and function in mononuclear and endothelial cells (ECs) of blood and lymph, we show that extracellular purines and CD73 activity have differential effects in these two vascular systems. We found that CD8-positive T lymphocytes and CD19-positive B lymphocytes in human lymph expressed high levels of CD73 and other purinergic enzymes and adenosine receptors. Soluble CD73 was less abundant in human lymph than in serum, whereas CD73 activity was higher in afferent lymphatic ECs than in blood ECs. Adenosine signaling improved barrier function and induced sprouting of human blood, but not lymphatic, ECs in vitro. Similarly, using CD73-deficient mice we found that CD73 controls only blood vascular permeability at selected lymphoid organs under physiological conditions. Thus, both vascular and lymphatic arms of the immune system synthesize the components of purinergic signaling system, but surprisingly they use CD73 differentially to control endothelial permeability and sprouting.Keywords: adenosine r endothelial cells r lymphatics r permeability r purinergic signaling See accompanying Commentary by Sidibé and Imhof.Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionPurinergic signaling plays a central role in controlling inflammation [1][2][3][4][5][6][7]. ATP and other purines are released to the cell Correspondence: Dr. Marko Salmi e-mail: marko.salmi@utu.fi exterior from intracellular pools both under physiological and pathological conditions via diverse pathways including exocytosis, specific channels, transporters, as well as cell death. On the cell surface extracellular ATP is sequentially hydrolyzed to ADP, AMP, * These authors contributed equally to this work.C 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2015. 45: 562-573 Molecular immunology 563 and adenosine through the action of specific ectonucleotidases [5]. Each of these purines can then bind to specific cell surface receptors and trigger intracellular signaling responses. Notably, ATP and ADP are proinflammatory and prothrombotic molecules, whereas adenosine usually exerts strong anti-inflammatory effects [4]. One rate-limiting enzyme in the purinergic signaling cascade is CD73/ecto-5 -nucleotidase, which converts AMP into adenosine [8,9]. CD73 is expressed on small subsets of lymphocytes, most notably on Treg cells, where it is crucial for the immunesuppressing functions [10]. CD73 is also present on endothelial cells (ECs). It is synthesized both on blood ECs (BECs) and lymphatic ECs (LECs). The role of CD73 on BECs in controlling vascular permeability and leukocyte trafficking is relatively well understood [11][12][13][14][15][16][17], but the function of lymphatic CD73 remains co...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Ecto‐5′‐nucleotidase/CD73 enhances endothelial barrier function and sprouting in blood but not lymphatic vasculature

et al. 2014

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“…Bakker and colleagues have reported increased glomerular expression of ecto-5′-nucleotidase in patients with chronic allograft nephropathy [57] and in those with glomerular ischaemia due to malignant hypertension [61]; increased activity of ecto-5′-nucleotidase in fibroblasts in the peritubular space of chronically hypoxic rats has also been reported [62]. A recent detailed study of the importance of ecto-5′-nucleotidase in protecting against renal ischaemia in mice demonstrated that short periods of ischaemic preconditioning caused increases in renal ecto-5′-nucleotidase mRNA and protein, and in renal tissue adenosine [63]. That these events were critical to the protective mechanisms was indicated by the findings that renal function after a subsequent period of renal ischaemia was severely compromised in mice subjected to either pharmacological inhibition of ecto-5′-nucleotidase or deletion of the gene encoding the enzyme [63].…”

Section: Renal Ectonucleotidases Under Pathological Conditionsmentioning

confidence: 99%

“…A recent detailed study of the importance of ecto-5′-nucleotidase in protecting against renal ischaemia in mice demonstrated that short periods of ischaemic preconditioning caused increases in renal ecto-5′-nucleotidase mRNA and protein, and in renal tissue adenosine [63]. That these events were critical to the protective mechanisms was indicated by the findings that renal function after a subsequent period of renal ischaemia was severely compromised in mice subjected to either pharmacological inhibition of ecto-5′-nucleotidase or deletion of the gene encoding the enzyme [63].…”

Section: Renal Ectonucleotidases Under Pathological Conditionsmentioning

confidence: 99%

Ectonucleotidases in the kidney

Shirley

Vekaria

Sévigny

2009

Purinergic Signalling

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Members of all four families of ectonucleotidases, namely ectonucleoside triphosphate diphosphohydrolases (NTPDases), ectonucleotide pyrophosphatase/ phosphodiesterases (NPPs), ecto-5′-nucleotidase and alkaline phosphatases, have been identified in the renal vasculature and/or tubular structures. In rats and mice, NTPDase1, which hydrolyses ATP through to AMP, is prominent throughout most of the renal vasculature and is also present in the thin ascending limb of Henle and medullary collecting duct. NTPDase2 and NTPDase3, which both prefer ATP over ADP as a substrate, are found in most nephron segments beyond the proximal tubule. NPPs catalyse not only the hydrolysis of ATP and ADP, but also of diadenosine polyphosphates. NPP1 has been identified in proximal and distal tubules of the mouse, while NPP3 is expressed in the rat glomerulus and pars recta, but not in more distal segments. Ecto-5′-nucleotidase, which catalyses the conversion of AMP to adenosine, is found in apical membranes of rat proximal convoluted tubule and intercalated cells of the distal nephron, as well as in the peritubular space. Finally, an alkaline phosphatase, which can theoretically catalyse the entire hydrolysis chain from nucleoside triphosphate to nucleoside, has been identified in apical membranes of rat proximal tubules; however, this enzyme exhibits relatively high K m values for adenine nucleotides. Although information on renal ectonucleotidases is still incomplete, the enzymes' varied distribution in the vasculature and along the nephron suggests that they can profoundly influence purinoceptor activity through the hydrolysis, and generation, of agonists of the various purinoceptor subtypes. This review provides an update on renal ectonucleotidases and speculates on the functional significance of these enzymes in terms of glomerular and tubular physiology and pathophysiology.

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“…Even though multiple attempts have been undertaken to identify molecular mechanisms that are involved in renal protection by Ischemic preconditioning, the underlying molecular mechanisms are largely unknown 4 . One way to increase the number of organs available for transplant is the improvement of grafts from DCD, as an alternative source to increase organ supply [5][6][7][8] .…”

Section: Introductionmentioning

confidence: 99%

The feasibility of an experimental model of donors after cardiac death in remote ischemic preconditioning studies for renal transplantation in porcine

Camarço

Morais²,

Moreno³

et al. 2014

Acta Cir. Bras.

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PURPOSE:To evaluate the feasibility of an experimental model of donors after cardiac death in remote ischemic preconditioning studies. METHODS:Twelve Landrace pigs were used as organ donors. They underwent cardiac arrest by coronary en block suture and interruption of ventilatory support. Haemodynamic data regarding the donor surgical protocol were evaluated. Studies variables included mean heart rate, systolic blood pressure, diastolic blood pressure, mean arterial pressure, central venous pressure and oxygen saturation and the time to death. RESULTS:Haemodynamic parameter indicated that the circulatory failure occurred after nine minutes of en block coronary suture and respiratory support interruption. The circulatory collapse occurred evenly across all groups. The heart rate and central venous pressure were statistically different between groups (p=0.023 and p=0.04), respectively. The remote preconditioning resulted in delayed time of death. CONCLUSIONS:The model is feasible, and was easily reproduced. The ischemic remote preconditioning tends to a slight increase in circulatory failure time.

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Protective Role of Ecto-5′-Nucleotidase (CD73) in Renal Ischemia

Cited by 144 publications

References 37 publications

Ecto‐5′‐nucleotidase/CD73 enhances endothelial barrier function and sprouting in blood but not lymphatic vasculature

Ecto‐5′‐nucleotidase/CD73 enhances endothelial barrier function and sprouting in blood but not lymphatic vasculature

Ectonucleotidases in the kidney

The feasibility of an experimental model of donors after cardiac death in remote ischemic preconditioning studies for renal transplantation in porcine

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