Adenosine provides anti-inflammatory effects in
cardiovascular disease via the activation of
adenosine A2A receptors; however, the physiological effect of
adenosine could be limited due to its phosphorylation by
adenosine kinase. We hypothesized that inhibition of
adenosine kinase exacerbates extracellular
adenosine levels to reduce renal
inflammation and injury in
streptozotocin-induced diabetes. Diabetes was induced in male C57BL/6 mice by daily injection of
streptozotocin (50mg/kg/day, i.p. for 5 days). Control and diabetic mice were then treated with the
adenosine kinase inhibitor
ABT702 (1.5mg/kg, i.p. two times a week for 8 weeks, n=7-8/group) or the vehicle (5%
DMSO).
ABT702 treatment reduced
blood glucose level in diabetic mice (∼20%; P<0.05).
ABT702 also reduced
albuminuria and markers of glomerular injury, nephrinuria and
podocalyxin excretion levels, in diabetic mice. Renal
NADPH oxidase activity and urinary
thiobarbituric acid reactive substances (
TBARS) excretion, indices of oxidative stress, were also elevated in diabetic mice and
ABT702 significantly reduced these changes.
ABT702 increased renal
endothelial nitric oxide synthase expression (eNOS) and
nitrate/
nitrite excretion levels in diabetic mice. In addition, the diabetic mice displayed an increase in renal macrophage infiltration, in association with increased renal NFκB activation. Importantly, treatment with
ABT702 significantly reduced all these inflammatory parameters (P<0.05). Furthermore,
ABT702 decreased glomerular permeability and
inflammation and restored the decrease in glomerular
occludin expression in vitro in high
glucose treated human glomerular endothelial cells. Collectively, the results suggest that the reno-protective effects of
ABT702 could be attributed to the reduction in renal
inflammation and oxidative stress in diabetic mice.