Equilibrative nucleoside transporter 1 (ENT1) regulates postischemic blood flow during acute kidney injury in mice
Almut Grenz, … , Michail Sitkovsky, Holger K. Eltzschig
Almut Grenz, … , Michail Sitkovsky, Holger K. Eltzschig
Published January 24, 2012
Citation Information: J Clin Invest. 2012;122(2):693-710. https://doi.org/10.1172/JCI60214.
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Research Article

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

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.

Authors

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. Blackburn, Hartmut Osswald, Imogen R. Coe, Bernd Nürnberg, Volker H. Haase, Yang Xia, Michail Sitkovsky, Holger K. Eltzschig

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Figure 6

Studies of ischemic AKI in Ent1 bone marrow chimeric mice or in Ent1–/– mice reconstituted with human ENT1.

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Studies of ischemic AKI in Ent1 bone marrow chimeric mice or in Ent1–/– ...
(A–D) Assessment of GFR, serum creatinine, MPO, and quantification of histologic tissue injury in Ent1 bone marrow chimeric mice (Control: sham-operated wild-type mice transplanted with wild-type bone marrow; KO: Ent1–/– mice; n = 4). (E) Ent1–/– kidneys were injected with saline or with a human ENT1-encoding lentivirus. After 24 hours, transcript levels of Ent1 were determined by real-time RT-PCR relative to β-actin (n = 4). (F–I) Assessment of renal adenosine, GFR, serum creatinine, and MPO tissue levels following 30 minutes of ischemia and indicated reperfusion times (n = 4).