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

Almut Grenz, Jessica D. Bauerle, Julee H. Dalton, Douglas Ridyard, Alexander Badulak, Eunyoung Tak, Eóin N. McNamee, Eric Clambey, Radu Moldovan, German Reyes, Jost Klawitter, Kelly Ambler, Kristann Magee, Uwe Christians, Kelley S. Brodsky, Katya Ravid, Doo Sup Choi, Jiaming Wen, Dmitriy Lukashev, Michael R. BlackburnHartmut Osswald, Imogen R. Coe, Bernd Nürnberg, Volker H. Haase, Yang Xia, Michail Sitkovsky, Holger K. Eltzschig

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)693-710
Number of pages18
JournalJournal of Clinical Investigation
Volume122
Issue number2
DOIs
StatePublished - Feb 2012

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Equilibrative Nucleoside Transporter 1
Acute Kidney Injury
Nucleoside Transport Proteins
Kidney
Adenosine
Purinergic P1 Receptors
Perfusion
Adenosine A2B Receptors
No-Reflow Phenomenon
Vascular Endothelium
Knockout Mice
Patient Care
Therapeutics
Ischemia

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Grenz, A., Bauerle, J. D., Dalton, J. H., Ridyard, D., Badulak, A., Tak, E., ... Eltzschig, H. K. (2012). Equilibrative nucleoside transporter 1 (ENT1) regulates postischemic blood flow during acute kidney injury in mice. Journal of Clinical Investigation, 122(2), 693-710. https://doi.org/10.1172/JCI60214

Equilibrative nucleoside transporter 1 (ENT1) regulates postischemic blood flow during acute kidney injury in mice. / Grenz, Almut; Bauerle, Jessica D.; Dalton, Julee H.; Ridyard, Douglas; Badulak, Alexander; Tak, Eunyoung; McNamee, Eóin N.; Clambey, Eric; Moldovan, Radu; Reyes, German; Klawitter, Jost; Ambler, Kelly; Magee, Kristann; Christians, Uwe; Brodsky, Kelley S.; Ravid, Katya; Choi, Doo Sup; Wen, Jiaming; Lukashev, Dmitriy; Blackburn, Michael R.; Osswald, Hartmut; Coe, Imogen R.; Nürnberg, Bernd; Haase, Volker H.; Xia, Yang; Sitkovsky, Michail; Eltzschig, Holger K.

In: Journal of Clinical Investigation, Vol. 122, No. 2, 02.2012, p. 693-710.

Research output: Contribution to journalArticle

Grenz, A, Bauerle, JD, Dalton, JH, Ridyard, D, Badulak, A, Tak, E, McNamee, EN, Clambey, E, Moldovan, R, Reyes, G, Klawitter, J, Ambler, K, Magee, K, Christians, U, Brodsky, KS, Ravid, K, Choi, DS, Wen, J, Lukashev, D, Blackburn, MR, Osswald, H, Coe, IR, Nürnberg, B, Haase, VH, Xia, Y, Sitkovsky, M & Eltzschig, HK 2012, 'Equilibrative nucleoside transporter 1 (ENT1) regulates postischemic blood flow during acute kidney injury in mice', Journal of Clinical Investigation, vol. 122, no. 2, pp. 693-710. https://doi.org/10.1172/JCI60214
Grenz, Almut ; Bauerle, Jessica D. ; Dalton, Julee H. ; Ridyard, Douglas ; Badulak, Alexander ; Tak, Eunyoung ; McNamee, Eóin N. ; Clambey, Eric ; Moldovan, Radu ; Reyes, German ; Klawitter, Jost ; Ambler, Kelly ; Magee, Kristann ; Christians, Uwe ; Brodsky, Kelley S. ; Ravid, Katya ; Choi, Doo Sup ; Wen, Jiaming ; Lukashev, Dmitriy ; Blackburn, Michael R. ; Osswald, Hartmut ; Coe, Imogen R. ; Nürnberg, Bernd ; Haase, Volker H. ; Xia, Yang ; Sitkovsky, Michail ; Eltzschig, Holger K. / Equilibrative nucleoside transporter 1 (ENT1) regulates postischemic blood flow during acute kidney injury in mice. In: Journal of Clinical Investigation. 2012 ; Vol. 122, No. 2. pp. 693-710.
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AU - Badulak, Alexander

AU - Tak, Eunyoung

AU - McNamee, Eóin N.

AU - Clambey, Eric

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AU - Reyes, German

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AU - Ambler, Kelly

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AU - Lukashev, Dmitriy

AU - Blackburn, Michael R.

AU - Osswald, Hartmut

AU - Coe, Imogen R.

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