title: 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.affiliation: Mucosal Inflammation Program, Department of Anesthesiology, School of Medicine, University of Colorado Denver, Anschutz Medical Campus, Aurora, Colorado, USA.
authors.forename: Almut
authors.initials: A
authors.lastname: Grenz
authors.forename: Jessica D
authors.initials: JD
authors.lastname: Bauerle
authors.forename: Julee H
authors.initials: JH
authors.lastname: Dalton
authors.forename: Douglas
authors.initials: D
authors.lastname: Ridyard
authors.forename: Alexander
authors.initials: A
authors.lastname: Badulak
authors.forename: Eunyoung
authors.initials: E
authors.lastname: Tak
authors.forename: Eóin N
authors.initials: EN
authors.lastname: McNamee
authors.forename: Eric
authors.initials: E
authors.lastname: Clambey
authors.forename: Radu
authors.initials: R
authors.lastname: Moldovan
authors.forename: German
authors.initials: G
authors.lastname: Reyes
authors.forename: Jost
authors.initials: J
authors.lastname: Klawitter
authors.forename: Kelly
authors.initials: K
authors.lastname: Ambler
authors.forename: Kristann
authors.initials: K
authors.lastname: Magee
authors.forename: Uwe
authors.initials: U
authors.lastname: Christians
authors.forename: Kelley S
authors.initials: KS
authors.lastname: Brodsky
authors.forename: Katya
authors.initials: K
authors.lastname: Ravid
authors.forename: Doo-Sup
authors.initials: DS
authors.lastname: Choi
authors.forename: Jiaming
authors.initials: J
authors.lastname: Wen
authors.forename: Dmitriy
authors.initials: D
authors.lastname: Lukashev
authors.forename: Michael R
authors.initials: MR
authors.lastname: Blackburn
authors.forename: Hartmut
authors.initials: H
authors.lastname: Osswald
authors.forename: Imogen R
authors.initials: IR
authors.lastname: Coe
authors.forename: Bernd
authors.initials: B
authors.lastname: Nürnberg
authors.forename: Volker H
authors.initials: VH
authors.lastname: Haase
authors.forename: Yang
authors.initials: Y
authors.lastname: Xia
authors.forename: Michail
authors.initials: M
authors.lastname: Sitkovsky
authors.forename: Holger K
authors.initials: HK
authors.lastname: Eltzschig
mesh_terms: D058186:Acute Kidney Injury / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D000241:Adenosine / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D046528:Chimerism; D004176:Dipyridamole / Q000627:therapeutic use; D033721:Equilibrative Nucleoside Transporter 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007511:Ischemia / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D054318:No-Reflow Phenomenon; D033703:Nucleoside Transport Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000627:therapeutic use; D018047:Receptors, Purinergic P1 / Q000235:genetics / Q000378:metabolism; D012039:Regional Blood Flow / Q000502:physiology*
chemical_list: D033721:Equilibrative Nucleoside Transporter 1; D033703:Nucleoside Transport Proteins; D010726:Phosphodiesterase Inhibitors; D018047:Receptors, Purinergic P1; C444719:adenosine transporter; D004176:Dipyridamole; D000241:Adenosine