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

Chelsey Pye, Nehal M. Elsherbiny, Ahmed Salah Ibrahim, Gregory I Liou, Ahmed Chadli, Mohamed Al-Shabrawey, Ahmed Abdelrazik Elmarakby

Research output: Contribution to journalArticle

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Abstract

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 (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 (∼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.

Original languageEnglish (US)
Pages (from-to)45-54
Number of pages10
JournalPharmacological Research
Volume85
DOIs
StatePublished - Jan 1 2014

Fingerprint

Adenosine Kinase
Experimental Diabetes Mellitus
Oxidants
Anti-Inflammatory Agents
Kidney
Adenosine
Inflammation
Oxidative Stress
Adenosine A2A Receptors
Occludin
Albuminuria
Thiobarbituric Acid Reactive Substances
Nitric Oxide Synthase Type III
NADPH Oxidase
Wounds and Injuries
Streptozocin
Nitrites
Dimethyl Sulfoxide
Inbred C57BL Mouse
Nitrates

Keywords

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

ASJC Scopus subject areas

  • Pharmacology

Cite this

Adenosine kinase inhibition protects the kidney against streptozotocin-induced diabetes through anti-inflammatory and anti-oxidant mechanisms. / Pye, Chelsey; Elsherbiny, Nehal M.; Ibrahim, Ahmed Salah; Liou, Gregory I; Chadli, Ahmed; Al-Shabrawey, Mohamed; Elmarakby, Ahmed Abdelrazik.

In: Pharmacological Research, Vol. 85, 01.01.2014, p. 45-54.

Research output: Contribution to journalArticle

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abstract = "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 (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 (∼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.",
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