4.7 Article

Adenosine kinase inhibition protects the kidney against streptozotocin-induced diabetes through anti-inflammatory and anti-oxidant mechanisms

Journal

PHARMACOLOGICAL RESEARCH
Volume 85, Issue -, Pages 45-54

Publisher

ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.phrs.2014.05.004

Keywords

Diabetes; Adenosine kinase inhibition; Albuminuria; Renal injury; Oxidative stress; Nitric oxide; Macrophage infiltration

Funding

  1. American Heart Association Scientist Development Grant (SDG) [1R01EY023315-01]

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Adenosine provides anti-inflammatory effects in cardiovascular disease via the activation of adenosine A(2A) 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 (50 mg/kg/day, i.p. for 5 days). Control and diabetic mice were then treated with the adenosine kinase inhibitor ABT702 (1.5 mg/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 (similar to 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 NF kappa B 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. (C) 2014 Elsevier Ltd. All rights reserved.

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