Renal ischemia and reperfusion during aortic and renal transplant surgery result in ischemic-reperfusion injury. Ischemic preconditioning and adenosine infusion before ischemia protect against ischemic-reperfusion injury in cardiac and skeletal muscle, but these protective phenomena have not been demonstrated in the kidney. Rats were randomized to sham operation, 45-min renal ischemia, ischemic preconditioning with four cycles of 8-min renal ischemia and 5-min reperfusion followed by 45-min renal ischemia, systemic adenosine pretreatment before 45-min renal ischemia, or pretreatments with selective adenosine receptor subtype agonists or antagonists before 45-min renal ischemia. Forty-five minutes of renal ischemia followed by 24 h of reperfusion resulted in marked rises in blood urea nitrogen and creatinine. Ischemic preconditioning and adenosine pretreatment protected renal function and improved renal morphology. A(1) adenosine receptor activation mimics and A(1) adenosine antagonism blocks adenosine-induced protection. In addition, A(3) adenosine receptor activation before renal ischemia worsens renal ischemic-reperfusion injury, and A(3) adenosine receptor antagonism protects renal function. We demonstrate for the first time that rat kidneys can be preconditioned to attenuate ischemic-reperfusion injury and adenosine infusion before ischemic insult protects renal function via A(1) adenosine receptor activation. Our data suggest that an A(1) adenosine agonist and A(3) adenosine antagonist may have clinically beneficial implications where renal ischemia is unavoidable.

Some volatile anesthetics confer profound protection against renal ischemia-reperfusion injury compared with pentobarbital or ketamine anesthesia by attenuating inflammation. These findings may have significant clinical implications for anesthesiologists regarding the choice of volatile anesthetic agents in patients subjected to perioperative renal ischemia.

Abstract. It was previously demonstrated that preischemic A 1 adenosine receptor (AR) activation protects renal function after ischemia-reperfusion (IR) injury in rats. The role of the A 1 AR in modulating inflammation, necrosis, and apoptosis in the kidney after IR renal injury was further characterized. C57BL/6 mice were subjected to 30 min of renal ischemia, with or without pretreatment with 1,3-dipropyl-8-cyclopentylxanthine or 2-chlorocyclopentyladenosine (selective A 1 AR antagonist and agonist, respectively). Plasma creatinine levels and renal inflammation, necrosis, and apoptosis were compared 24 h after renal injury. C57BL/6 mice that had been pretreated with the A 1 AR agonist demonstrated significantly improved renal function and reduced expression of inflammatory markers, necrosis, and apoptosis 24 h after IR injury. In contrast, C57BL/6 mice that had been pretreated with the A 1 AR antagonist demonstrated significantly worsened renal function and increased expression of inflammatory markers, necrosis, and apoptosis. In conclusion, it was demonstrated that endogenous and exogenous preischemic activation of the A 1 AR protects against IR injury in vivo, through mechanisms that reduce inflammation, necrosis, and apoptosis.Acute renal failure (ARF) secondary to ischemia-reperfusion (IR) injury continues to be a significant perioperative problem. ARF is frequently complicated by many other life-threatening complications, including sepsis and multiorgan failure. The prognosis for ARF is poor (with mortality rates of approximately 50%) and has changed little in the past 40 yr (1-3).We previously demonstrated that pharmacologic adenosine receptor (AR) modulation significantly affects renal function after IR injury in rats (4 -6). In particular, we demonstrated that preischemic activation of the A 1 AR attenuated renal failure after IR injury in vivo (4). We also demonstrated the cytoprotective effects of A 1 AR activation in cultured proximal tubule cells injured by H 2 O 2 or severe ATP depletion (7,8).Modulation of AR has been demonstrated to attenuate necrosis (9), inflammation (10,11), and apoptosis (12,13) after injury. Both apoptosis and necrosis contribute significantly to the pathogenesis of ARF after IR injury (14,15). Moreover, inflammatory renal injury is a significant component of necrotic renal cell death (16,17). It remains to be determined whether the renoprotective effect of preischemic A 1 AR activation is associated with modulation of apoptosis, necrosis, and/or inflammation. Therefore, in this study, we aimed to extend our previous findings regarding the mechanisms of A 1 AR effects on renal function after IR injury. We questioned whether the protective effects of A 1 AR activation were mediated through a decrease in the inflammatory response in the kidney and whether necrotic or apoptotic cell death was attenuated. We hypothesized that preischemic activation or inhibition of A 1 AR would decrease or increase levels of inflammation markers, respectively. Moreover, we hypothesized that nec...

A 1 adenosine receptor knockout mice exhibit increased renal injury following ischemia and reperfusion. Am

In Alzheimer's disease (AD) and other tauopathies, the microtubule-associated protein tau can undergo aberrant hyperphosphorylation potentially leading to the development of neurofibrillary pathology. Anesthetics have been previously shown to induce tau hyperphosphorylation through a mechanism involving hypothermia-induced inhibition of protein phosphatase 2A (PP2A) activity. However, the effects of propofol, a common clinically used intravenous anesthetic, on tau phosphorylation under normothermic conditions are unknown. We investigated the effects of a general anesthetic dose of propofol on levels of phosphorylated tau in the mouse hippocampus and cortex under normothermic conditions. Thirty min following the administration of propofol 250 mg/kg i.p., significant increases in tau phosphorylation were observed at the AT8, CP13, and PHF-1 phosphoepitopes in the hippocampus, as well as at AT8, PHF-1, MC6, pS262, and pS422 epitopes in the cortex. However, we did not detect somatodendritic relocalization of tau. In both brain regions, tau hyperphosphorylation persisted at the AT8 epitope 2 h following propofol, although the sedative effects of the drug were no longer evident at this time point. By 6 h following propofol, levels of phosphorylated tau at AT8 returned to control levels. An initial decrease in the activity and expression of PP2A were observed, suggesting that PP2A inhibition is at least partly responsible for the hyperphosphorylation of tau at multiple sites following 30 min of propofol exposure. We also examined tau phosphorylation in SH-SY5Y cells transfected to overexpress human tau. A 1 h exposure to a clinically relevant concentration of propofol in vitro was also associated with tau hyperphosphorylation. These findings suggest that propofol increases tau phosphorylation both in vivo and in vitro under normothermic conditions, and further studies are warranted to determine the impact of this anesthetic on the acceleration of neurofibrillary pathology.