Adenosine kinase inhibition protects the kidney against streptozotocin-induced diabetes through anti-inflammatory and anti-oxidant mechanisms.
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.
Department of Oral Biology, Georgia Regents University, Augusta, GA 30912, United States.
Chelsey
C
Pye
Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt.
Nehal M
NM
Elsherbiny
Department of Oral Biology, Georgia Regents University, Augusta, GA 30912, United States; Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt.
Ahmed S
AS
Ibrahim
Department of Ophthalmology, Georgia Regents University, Augusta, GA 30912, United States.
Gregory I
GI
Liou
Center for Molecular Chaperones/Radiobiology and Cancer Virology, Georgia Regents University, Augusta, GA 30912, United States.
Ahmed
A
Chadli
Department of Oral Biology, Georgia Regents University, Augusta, GA 30912, United States.
Mohamed
M
Al-Shabrawey
Department of Oral Biology, Georgia Regents University, Augusta, GA 30912, United States; Department of Pharmacology & Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt. Electronic address: aelmarakby@gru.edu.
Ahmed A
AA
Elmarakby
D000248:Adenosine Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000975:Antioxidants / Q000494:pharmacology* / Q000627:therapeutic use; D001786:Blood Glucose / Q000032:analysis; D002460:Cell Line; D003911:Dextrans / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D016650:Fluorescein-5-isothiocyanate / Q000031:analogs & derivatives / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology* / Q000627:therapeutic use; D019255:NADPH Oxidases / Q000378:metabolism; D009566:Nitrates / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D011507:Proteinuria / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D001786:Blood Glucose; D003911:Dextrans; D009025:Morpholines; D009566:Nitrates; D009573:Nitrites; D011743:Pyrimidines; D017392:Thiobarbituric Acid Reactive Substances; D051996:Transcription Factor RelA; C015219:fluorescein isothiocyanate dextran; C416933:ABT 702; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D019255:NADPH Oxidases; D000248:Adenosine Kinase; D020928:Mitogen-Activated Protein Kinases; D016650:Fluorescein-5-isothiocyanate
Adenosine kinase inhibition; Albuminuria; Diabetes; Macrophage infiltration; Nitric oxide; Oxidative stress; Renal injury