adenosine-kinase and Necrosis

Acute kidney injury (AKI) has a high morbidity and mortality, and there is no targeted treatment yet. One of the main causes of AKI is ischemia-reperfusion (IR). Increased release of adenosine under stress and hypoxia exerts anti-inflammatory and antioxidant effects. Adenosine kinase (ADK) is an important enzyme that eliminates adenosine in cells, and can maintain low adenosine concentration in cells. Our previous studies have shown that pretreatment of adenosine kinase inhibitor ABT-702 could markedly attenuate cisplatin-induced nephrotoxicity both in vivo and in vitro. This study is designed to investigate the effect of ADK inhibition on IR-induced AKI. The results showed that ADK expression was positively correlated with the degree of renal tubular injury, which suggested that the degree of ADK inhibition reflected the severity of acute tubular necrosis. In vivo, ADK inhibitor could reduce IR-induced renal injury, which might play a protective role by increasing tissue adenosine level, inhibiting oxidative stress, and reducing cell apoptosis. In HK2 cells, cobaltous dichloride (CoCl

Topics: Acute Kidney Injury; Adenosine Kinase; Adult; Animals; Apoptosis; Cell Line; Cobalt; Enzyme Inhibitors; Female; Humans; Inflammation; Inosine; Kidney Tubules; Male; Mice, Inbred C57BL; Morpholines; Necrosis; Oxidative Stress; Pyrimidines; Reperfusion Injury

We investigated the roles of A1, A2A, or A3 receptors and purine salvage in cardioprotection with exogenous adenosine, and tested whether A2A -mediated reductions in perfusion pressure modify post-ischemic recovery. Treatment with 10(-5) or 5 x 10(-5) M adenosine improved contractile recovery from 20 min ischemia 45 min reperfusion in isolated mouse hearts. Protection was attenuated by adenosine kinase inhibition (10(-5) M iodotubercidin) and receptor antagonism (5 x 10(-5) M 8-rho-sulfophenyltheophylline, 8-SPT). Enzyme efflux mirrored contractile recoveries. A 3 agonism with 10(-7) M 2-chloro- N6-(3-iodobenzyl)-adenosine-5'-N-methyluronamide (Cl-IB-MECA) improved ischemic tolerance whereas A1 agonism with 5 x 10(-8) M N6-cyclopentyladenosine (CPA) and A2A agonism with 10(-9) M 2-[p-(2-carboxyethyl) phenethylamino]-5'-N-ethylcarboxamidoadenosine (CGS21680) or 2 x 10(-8) M methyl-4-(3-[9-[4S,5S,2R,3R)-5-(N-ethylcarbamoyl)-3,4-dihydroxyoxolan-2-yl]-6-aminopurin-2-yl)]prop-2-ynyl) cyclohexane-carboxylate (ATL-146e) were ineffective. Protection via A1 receptor overexpression was enhanced by adenosine, but unaltered by A1 or A2A agonists. Finally, post-ischemic dysfunction in hearts perfused at constant flow was dependent on coronary pressure, with A2A AR-mediated reductions in pressure reducing diastolic contracture, and elevated perfusion pressure worsening contracture. Data indicate that cardioprotection with exogenous adenosine in asanguinous hearts involves purine salvage and activation of A3 but not A1 or A2A receptors.

Topics: Adenosine; Adenosine Kinase; Animals; Blood Pressure; Cardiotonic Agents; Coronary Circulation; Female; In Vitro Techniques; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Myocardial Reperfusion Injury; Myocardium; Necrosis; Phosphorylation; Purinergic P1 Receptor Agonists; Receptor, Adenosine A2A; Receptors, Purinergic P1; Vasodilator Agents; Ventricular Pressure