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Departments of 1 Medicine and 2 Chemistry, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908
A2A adenosine receptors
(A2A-ARs) are known modulators of
renal hemodynamics and potent inhibitors of inflammation. We sought to
determine whether selective activation of
A2A-ARs protects kidneys from
ischemia-reperfusion injury. The ester derivative of DWH-146
(DWH-146e), a selective
A2A agonist, was found to be more
potent and selective for A2A-ARs
than the prototype compound CGS-21680. Osmotic minipumps were implanted
subcutaneously to infuse into rats either vehicle or DWH-146e (0.004 µg · kg
1 · min1),
during and after ischemia-reperfusion injury. Following 24 and
48 h of reperfusion, the rise in serum creatinine and blood urea
nitrogen for vehicle-treated rats was substantially elevated compared
with DWH-146e-treated rats. Histological examination revealed
widespread tubular epithelial necrosis and vascular congestion in the
outer medulla of vehicle-treated compared with DWH-146e-treated animals. ZM-241385, a selective
A2A antagonist, blocked the
protective effect of DWH-146e. Delaying administration of DWH-146e
until the initiation of reperfusion also decreased serum creatinine. We
conclude that 1) selective
A2A-AR activation by DWH-146e
reduces ischemia-reperfusion injury in rat kidneys,
2) the effect of DWH-146e is
A2A receptor mediated, and
3) the protective effects are
mediated by preventing injury during the reperfusion period.
acute renal failure; ischemia; inflammation; DWH-146 ester; ZM-241385
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